Federal Practitioner

Key clinical point: Hampered ultrasound visualization in patients with cirrhosis receiving hepatocellular carcinoma (HCC) surveillance is associated with worse test performance, negatively affecting both sensitivity and specificity of surveillance.

Major finding: Patients with cirrhosis and HCC having severely impaired ultrasound visualization before HCC diagnosis showed increased odds of false-negative results (adjusted odds ratio [aOR] 7.94; 95% CI 1.23-51.16), whereas those with only cirrhosis having moderately impaired visualization showed increased odds of false-positive results (aOR 1.60; 95% CI 1.13-2.27).

Study details: This was a retrospective cohort study involving 2,238 patients with cirrhosis, with (n = 186) or without (n = 2,052) HCC, who underwent at least one abdominal ultrasound examination.

Disclosures: The study was supported by the United States National Institute of Health. A Singal and D Fetzer declared serving as consultants or advisory board members of or having research agreements with various organizations.

Source: Chong N et al. Association between ultrasound quality and test performance for HCC surveillance in patients with cirrhosis: a retrospective cohort study. Aliment Pharmacol Ther. 2022;55(6):683-690 (Feb 15). Doi: 10.1111/apt.16779

Key clinical point: Hampered ultrasound visualization in patients with cirrhosis receiving hepatocellular carcinoma (HCC) surveillance is associated with worse test performance, negatively affecting both sensitivity and specificity of surveillance.

Major finding: Patients with cirrhosis and HCC having severely impaired ultrasound visualization before HCC diagnosis showed increased odds of false-negative results (adjusted odds ratio [aOR] 7.94; 95% CI 1.23-51.16), whereas those with only cirrhosis having moderately impaired visualization showed increased odds of false-positive results (aOR 1.60; 95% CI 1.13-2.27).

Study details: This was a retrospective cohort study involving 2,238 patients with cirrhosis, with (n = 186) or without (n = 2,052) HCC, who underwent at least one abdominal ultrasound examination.

Disclosures: The study was supported by the United States National Institute of Health. A Singal and D Fetzer declared serving as consultants or advisory board members of or having research agreements with various organizations.

Source: Chong N et al. Association between ultrasound quality and test performance for HCC surveillance in patients with cirrhosis: a retrospective cohort study. Aliment Pharmacol Ther. 2022;55(6):683-690 (Feb 15). Doi: 10.1111/apt.16779

Key clinical point: Hampered ultrasound visualization in patients with cirrhosis receiving hepatocellular carcinoma (HCC) surveillance is associated with worse test performance, negatively affecting both sensitivity and specificity of surveillance.

Major finding: Patients with cirrhosis and HCC having severely impaired ultrasound visualization before HCC diagnosis showed increased odds of false-negative results (adjusted odds ratio [aOR] 7.94; 95% CI 1.23-51.16), whereas those with only cirrhosis having moderately impaired visualization showed increased odds of false-positive results (aOR 1.60; 95% CI 1.13-2.27).

Study details: This was a retrospective cohort study involving 2,238 patients with cirrhosis, with (n = 186) or without (n = 2,052) HCC, who underwent at least one abdominal ultrasound examination.

Disclosures: The study was supported by the United States National Institute of Health. A Singal and D Fetzer declared serving as consultants or advisory board members of or having research agreements with various organizations.

Source: Chong N et al. Association between ultrasound quality and test performance for HCC surveillance in patients with cirrhosis: a retrospective cohort study. Aliment Pharmacol Ther. 2022;55(6):683-690 (Feb 15). Doi: 10.1111/apt.16779

Key clinical point: Magnetic resonance elastography (MRE)-based shear strain mapping may serve as a noninvasive biomarker enabling the characterization of the tumor-liver interface and preoperative prediction of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC).

Major finding: The positive MVI vs. negative MVI group displayed a significantly higher octahedral shear strain (OSS) percentage of low-shear-strain length (pLSL) at three evaluation frequencies (60 Hz: 75% vs. 40%, 40 Hz: 85% vs. 40%, and 30 Hz: 70% vs. 20%; all P < .01). The peritumor OSS-pLSL area under the receiver operating characteristic curve (0.73-0.90) for MVI prediction was good/excellent at all frequencies.

Study details: The data are derived from a retrospective study of 59 patients with HCC, all of whom underwent the conventional 60 Hz MRE examination; of these, 29 patients also underwent 40 and 30 Hz MRE examinations.

Disclosures: The study was funded by the National Natural Science Foundation of China, among others. The authors declared no conflict of interests.

Source: Li M et al. MR elastography-based shear strain mapping for assessment of microvascular invasion in hepatocellular carcinoma. Eur Radiol. 2022 (Feb 11). Doi: 10.1007/s00330-022-08578-w

Key clinical point: Magnetic resonance elastography (MRE)-based shear strain mapping may serve as a noninvasive biomarker enabling the characterization of the tumor-liver interface and preoperative prediction of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC).

Major finding: The positive MVI vs. negative MVI group displayed a significantly higher octahedral shear strain (OSS) percentage of low-shear-strain length (pLSL) at three evaluation frequencies (60 Hz: 75% vs. 40%, 40 Hz: 85% vs. 40%, and 30 Hz: 70% vs. 20%; all P < .01). The peritumor OSS-pLSL area under the receiver operating characteristic curve (0.73-0.90) for MVI prediction was good/excellent at all frequencies.

Study details: The data are derived from a retrospective study of 59 patients with HCC, all of whom underwent the conventional 60 Hz MRE examination; of these, 29 patients also underwent 40 and 30 Hz MRE examinations.

Disclosures: The study was funded by the National Natural Science Foundation of China, among others. The authors declared no conflict of interests.

Source: Li M et al. MR elastography-based shear strain mapping for assessment of microvascular invasion in hepatocellular carcinoma. Eur Radiol. 2022 (Feb 11). Doi: 10.1007/s00330-022-08578-w

Key clinical point: Magnetic resonance elastography (MRE)-based shear strain mapping may serve as a noninvasive biomarker enabling the characterization of the tumor-liver interface and preoperative prediction of microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC).

Major finding: The positive MVI vs. negative MVI group displayed a significantly higher octahedral shear strain (OSS) percentage of low-shear-strain length (pLSL) at three evaluation frequencies (60 Hz: 75% vs. 40%, 40 Hz: 85% vs. 40%, and 30 Hz: 70% vs. 20%; all P < .01). The peritumor OSS-pLSL area under the receiver operating characteristic curve (0.73-0.90) for MVI prediction was good/excellent at all frequencies.

Study details: The data are derived from a retrospective study of 59 patients with HCC, all of whom underwent the conventional 60 Hz MRE examination; of these, 29 patients also underwent 40 and 30 Hz MRE examinations.

Disclosures: The study was funded by the National Natural Science Foundation of China, among others. The authors declared no conflict of interests.

Source: Li M et al. MR elastography-based shear strain mapping for assessment of microvascular invasion in hepatocellular carcinoma. Eur Radiol. 2022 (Feb 11). Doi: 10.1007/s00330-022-08578-w

Key clinical point: Patients with advanced hepatocellular carcinoma (aHCC) and alpha-fetoprotein (AFP) levels ≥400 ng/mL experience a consistent survival benefit with ramucirumab therapy irrespective of baseline prognostic covariates.

Major finding: Ramucirumab vs. placebo improved overall survival in patients with viral (hazard ratio [HR] 0.76; 95% CI 0.60-0.97) and nonviral (HR 0.56; 95% CI 0.49-0.79) etiologies and in those with above-median AFP levels (≥4,081.5 ng/mL; HR 0.71; 95% CI 0.54-0.95).

Study details: Findings are from a post hoc meta-analysis of the phase 3 REACH and REACH-2 trials involving 542 patients with aHCC and AFP levels ≥400 ng/mL who were randomly assigned to receive ramucirumab (n = 316) or placebo (n = 226).

Disclosures: The study was sponsored by Eli Lilly and Company. JM Llovet, A Singal, A Villanueva, R Finn, M Kudo, P Galle, M Ikeda, and A Zhu reported receiving grants, personal/advisory board/consulting fees, or honoraria from various sources, including Eli Lilly. The other authors are employees or shareholders of Eli Lilly.

Source: Llovet JM et al. Prognostic and predictive factors in patients with advanced HCC and elevated alpha-fetoprotein treated with ramucirumab in two randomized phase III trial. Clin Cancer Res. 2022 (Mar 4). Doi: 10.1158/1078-0432.CCR-21-4000

Key clinical point: Patients with advanced hepatocellular carcinoma (aHCC) and alpha-fetoprotein (AFP) levels ≥400 ng/mL experience a consistent survival benefit with ramucirumab therapy irrespective of baseline prognostic covariates.

Major finding: Ramucirumab vs. placebo improved overall survival in patients with viral (hazard ratio [HR] 0.76; 95% CI 0.60-0.97) and nonviral (HR 0.56; 95% CI 0.49-0.79) etiologies and in those with above-median AFP levels (≥4,081.5 ng/mL; HR 0.71; 95% CI 0.54-0.95).

Study details: Findings are from a post hoc meta-analysis of the phase 3 REACH and REACH-2 trials involving 542 patients with aHCC and AFP levels ≥400 ng/mL who were randomly assigned to receive ramucirumab (n = 316) or placebo (n = 226).

Disclosures: The study was sponsored by Eli Lilly and Company. JM Llovet, A Singal, A Villanueva, R Finn, M Kudo, P Galle, M Ikeda, and A Zhu reported receiving grants, personal/advisory board/consulting fees, or honoraria from various sources, including Eli Lilly. The other authors are employees or shareholders of Eli Lilly.

Source: Llovet JM et al. Prognostic and predictive factors in patients with advanced HCC and elevated alpha-fetoprotein treated with ramucirumab in two randomized phase III trial. Clin Cancer Res. 2022 (Mar 4). Doi: 10.1158/1078-0432.CCR-21-4000

Key clinical point: Patients with advanced hepatocellular carcinoma (aHCC) and alpha-fetoprotein (AFP) levels ≥400 ng/mL experience a consistent survival benefit with ramucirumab therapy irrespective of baseline prognostic covariates.

Major finding: Ramucirumab vs. placebo improved overall survival in patients with viral (hazard ratio [HR] 0.76; 95% CI 0.60-0.97) and nonviral (HR 0.56; 95% CI 0.49-0.79) etiologies and in those with above-median AFP levels (≥4,081.5 ng/mL; HR 0.71; 95% CI 0.54-0.95).

Study details: Findings are from a post hoc meta-analysis of the phase 3 REACH and REACH-2 trials involving 542 patients with aHCC and AFP levels ≥400 ng/mL who were randomly assigned to receive ramucirumab (n = 316) or placebo (n = 226).

Disclosures: The study was sponsored by Eli Lilly and Company. JM Llovet, A Singal, A Villanueva, R Finn, M Kudo, P Galle, M Ikeda, and A Zhu reported receiving grants, personal/advisory board/consulting fees, or honoraria from various sources, including Eli Lilly. The other authors are employees or shareholders of Eli Lilly.

Source: Llovet JM et al. Prognostic and predictive factors in patients with advanced HCC and elevated alpha-fetoprotein treated with ramucirumab in two randomized phase III trial. Clin Cancer Res. 2022 (Mar 4). Doi: 10.1158/1078-0432.CCR-21-4000

Key clinical point: Compared with patients with hepatocellular carcinoma (HCC) due to other causes, a higher proportion of those with nonalcoholic fatty liver disease (NAFLD)-related HCC do not have cirrhosis and lack an indication for HCC surveillance, thus calling for surveillance strategies for patients with NAFLD without cirrhosis but at high risk for HCC.

Major finding: The proportion of patients without cirrhosis was higher among those with NAFLD-related HCC vs. HCC due to other causes (38.5% vs. 14.6%; P < .0001). Before cancer diagnosis, only 32.8% of patients with NAFLD-related HCC underwent HCC surveillance relative to 55.7% of those with HCC due to other causes (odds ratio 0.36; P < .0001).

Study details: This was a meta-analysis of 61 studies including 94,636 patients with HCC related to either NAFLD (n = 15,377) or other causes (n = 79,259).

Disclosures: No funding was received for the study. Some authors declared having stock options from, serving as paid/unpaid consultants or advisory board members for, and receiving royalties or research grants from various organizations.

Source: Tan DJH et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol. 2022 (Mar 4). Doi: 10.1016/S1470-2045(22)00078-X

Key clinical point: Compared with patients with hepatocellular carcinoma (HCC) due to other causes, a higher proportion of those with nonalcoholic fatty liver disease (NAFLD)-related HCC do not have cirrhosis and lack an indication for HCC surveillance, thus calling for surveillance strategies for patients with NAFLD without cirrhosis but at high risk for HCC.

Major finding: The proportion of patients without cirrhosis was higher among those with NAFLD-related HCC vs. HCC due to other causes (38.5% vs. 14.6%; P < .0001). Before cancer diagnosis, only 32.8% of patients with NAFLD-related HCC underwent HCC surveillance relative to 55.7% of those with HCC due to other causes (odds ratio 0.36; P < .0001).

Study details: This was a meta-analysis of 61 studies including 94,636 patients with HCC related to either NAFLD (n = 15,377) or other causes (n = 79,259).

Disclosures: No funding was received for the study. Some authors declared having stock options from, serving as paid/unpaid consultants or advisory board members for, and receiving royalties or research grants from various organizations.

Source: Tan DJH et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol. 2022 (Mar 4). Doi: 10.1016/S1470-2045(22)00078-X

Key clinical point: Compared with patients with hepatocellular carcinoma (HCC) due to other causes, a higher proportion of those with nonalcoholic fatty liver disease (NAFLD)-related HCC do not have cirrhosis and lack an indication for HCC surveillance, thus calling for surveillance strategies for patients with NAFLD without cirrhosis but at high risk for HCC.

Major finding: The proportion of patients without cirrhosis was higher among those with NAFLD-related HCC vs. HCC due to other causes (38.5% vs. 14.6%; P < .0001). Before cancer diagnosis, only 32.8% of patients with NAFLD-related HCC underwent HCC surveillance relative to 55.7% of those with HCC due to other causes (odds ratio 0.36; P < .0001).

Study details: This was a meta-analysis of 61 studies including 94,636 patients with HCC related to either NAFLD (n = 15,377) or other causes (n = 79,259).

Disclosures: No funding was received for the study. Some authors declared having stock options from, serving as paid/unpaid consultants or advisory board members for, and receiving royalties or research grants from various organizations.

Source: Tan DJH et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol. 2022 (Mar 4). Doi: 10.1016/S1470-2045(22)00078-X

Key clinical point: Lenvatinib (LEN)-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy may be more clinically beneficial than LEN monotherapy in patients with unresectable hepatocellular carcinoma (HCC) responsive to initial LEN treatment without exerting any additional adverse effects.

Major finding: The LEN-TACE vs. LEN monotherapy group showed a significantly higher median overall survival (31.2 months vs. 13.9 months; P = .002) and progression-free survival (12.2 months vs. 7.1 months; P = .037). The LEN-TACE group had an acceptable safety profile, with only liver dysfunction being significantly higher (P = .04).

Study details: Findings are from a retrospective, multicenter cohort study on patients with intermediate- or advanced-stage unresectable HCC who responded to initial LEN treatment. Among these, 63 patients receiving LEN-TACE sequential therapy were propensity-score matched to those receiving LEN monotherapy.

Disclosures: The authors declared no source of funding or conflict of interests.

Source: Kuroda H et al. Objective response by mRECIST to initial lenvatinib therapy is an independent factor contributing to deep response in hepatocellular carcinoma treated with lenvatinib-transcatheter arterial chemoembolization sequential therapy. Liver Cancer. 2022 (Feb 15). Doi: 10.1159/000522424

Key clinical point: Lenvatinib (LEN)-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy may be more clinically beneficial than LEN monotherapy in patients with unresectable hepatocellular carcinoma (HCC) responsive to initial LEN treatment without exerting any additional adverse effects.

Major finding: The LEN-TACE vs. LEN monotherapy group showed a significantly higher median overall survival (31.2 months vs. 13.9 months; P = .002) and progression-free survival (12.2 months vs. 7.1 months; P = .037). The LEN-TACE group had an acceptable safety profile, with only liver dysfunction being significantly higher (P = .04).

Study details: Findings are from a retrospective, multicenter cohort study on patients with intermediate- or advanced-stage unresectable HCC who responded to initial LEN treatment. Among these, 63 patients receiving LEN-TACE sequential therapy were propensity-score matched to those receiving LEN monotherapy.

Disclosures: The authors declared no source of funding or conflict of interests.

Source: Kuroda H et al. Objective response by mRECIST to initial lenvatinib therapy is an independent factor contributing to deep response in hepatocellular carcinoma treated with lenvatinib-transcatheter arterial chemoembolization sequential therapy. Liver Cancer. 2022 (Feb 15). Doi: 10.1159/000522424

Key clinical point: Lenvatinib (LEN)-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy may be more clinically beneficial than LEN monotherapy in patients with unresectable hepatocellular carcinoma (HCC) responsive to initial LEN treatment without exerting any additional adverse effects.

Major finding: The LEN-TACE vs. LEN monotherapy group showed a significantly higher median overall survival (31.2 months vs. 13.9 months; P = .002) and progression-free survival (12.2 months vs. 7.1 months; P = .037). The LEN-TACE group had an acceptable safety profile, with only liver dysfunction being significantly higher (P = .04).

Study details: Findings are from a retrospective, multicenter cohort study on patients with intermediate- or advanced-stage unresectable HCC who responded to initial LEN treatment. Among these, 63 patients receiving LEN-TACE sequential therapy were propensity-score matched to those receiving LEN monotherapy.

Disclosures: The authors declared no source of funding or conflict of interests.

Source: Kuroda H et al. Objective response by mRECIST to initial lenvatinib therapy is an independent factor contributing to deep response in hepatocellular carcinoma treated with lenvatinib-transcatheter arterial chemoembolization sequential therapy. Liver Cancer. 2022 (Feb 15). Doi: 10.1159/000522424

Key clinical point: Although treatment with transarterial chemoembolization (TACE) plus sorafenib does not significantly increase overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) relative to TACE alone, it does offer a clinically meaningful OS prolongation.

Major finding: Patients receiving TACE plus sorafenib vs. TACE monotherapy showed a median OS of 36.2 months vs. 30.8 months (hazard ratio 0.861; P = .40). Despite being nonsignificant, the benefit (ΔOS 5.4 months) was clinically meaningful.

Study details: The data represent the final results of the multicenter, prospective phase 2 TACTICS trial including 156 patients aged >20 years with unresectable HCC having a life expectancy of ≥12 weeks who were randomly assigned to TACE plus sorafenib (n = 80) or TACE alone (n = 76).

Disclosures: The study was sponsored by Bayer Yakuhin Ltd., Japan. Some authors reported serving as speakers/advisory consultants for and receiving grants, personal fees, and consulting/advisory fees from various sources including Bayer. M Kudo is the Editor-in-Chief of Liver Cancer, and some others are its editorial board members.

Source: Kudo M et al. Final results of TACTICS: A randomized, prospective trial comparing transarterial chemoembolization plus sorafenib to transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma. Liver Cancer. 2022 (Feb 10). Doi: 10.1159/000522547

Key clinical point: Although treatment with transarterial chemoembolization (TACE) plus sorafenib does not significantly increase overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) relative to TACE alone, it does offer a clinically meaningful OS prolongation.

Major finding: Patients receiving TACE plus sorafenib vs. TACE monotherapy showed a median OS of 36.2 months vs. 30.8 months (hazard ratio 0.861; P = .40). Despite being nonsignificant, the benefit (ΔOS 5.4 months) was clinically meaningful.

Study details: The data represent the final results of the multicenter, prospective phase 2 TACTICS trial including 156 patients aged >20 years with unresectable HCC having a life expectancy of ≥12 weeks who were randomly assigned to TACE plus sorafenib (n = 80) or TACE alone (n = 76).

Disclosures: The study was sponsored by Bayer Yakuhin Ltd., Japan. Some authors reported serving as speakers/advisory consultants for and receiving grants, personal fees, and consulting/advisory fees from various sources including Bayer. M Kudo is the Editor-in-Chief of Liver Cancer, and some others are its editorial board members.

Source: Kudo M et al. Final results of TACTICS: A randomized, prospective trial comparing transarterial chemoembolization plus sorafenib to transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma. Liver Cancer. 2022 (Feb 10). Doi: 10.1159/000522547

Key clinical point: Although treatment with transarterial chemoembolization (TACE) plus sorafenib does not significantly increase overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC) relative to TACE alone, it does offer a clinically meaningful OS prolongation.

Major finding: Patients receiving TACE plus sorafenib vs. TACE monotherapy showed a median OS of 36.2 months vs. 30.8 months (hazard ratio 0.861; P = .40). Despite being nonsignificant, the benefit (ΔOS 5.4 months) was clinically meaningful.

Study details: The data represent the final results of the multicenter, prospective phase 2 TACTICS trial including 156 patients aged >20 years with unresectable HCC having a life expectancy of ≥12 weeks who were randomly assigned to TACE plus sorafenib (n = 80) or TACE alone (n = 76).

Disclosures: The study was sponsored by Bayer Yakuhin Ltd., Japan. Some authors reported serving as speakers/advisory consultants for and receiving grants, personal fees, and consulting/advisory fees from various sources including Bayer. M Kudo is the Editor-in-Chief of Liver Cancer, and some others are its editorial board members.

Source: Kudo M et al. Final results of TACTICS: A randomized, prospective trial comparing transarterial chemoembolization plus sorafenib to transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma. Liver Cancer. 2022 (Feb 10). Doi: 10.1159/000522547

Key clinical point: Patients receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) after curative liver resection for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) showed significantly better overall survival and protection of liver function but no significant difference in the cumulative incidences of HCC recurrence.

Major finding: Although patients receiving TDF vs. ETV showed no significant difference in recurrence-free survival after propensity-score matching (hazard ratio [HR] 0.91; P = .45), they had significantly better overall survival (HR 0.37; P = .002) and liver function (P = .001).

Study details: This retrospective, single-center study reviewed data on 1,173 adult patients with HBV-related HCC who had undergone liver resection and were initially treated with either TDF or ETV for chronic HBV infection.

Disclosures: The study was funded by Sun Yat-sen University Cancer Center physician-scientist funding and National Science and Technology Major Project of China. The authors reported having no conflict of interests.

Source: Wang XH et al. Tenofovir vs. entecavir on prognosis of hepatitis B virus-related hepatocellular carcinoma after curative resection. J Gastroenterol. 2022;57:185-198 (Feb 13). Doi: 10.1007/s00535-022-01855-x

Key clinical point: Patients receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) after curative liver resection for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) showed significantly better overall survival and protection of liver function but no significant difference in the cumulative incidences of HCC recurrence.

Major finding: Although patients receiving TDF vs. ETV showed no significant difference in recurrence-free survival after propensity-score matching (hazard ratio [HR] 0.91; P = .45), they had significantly better overall survival (HR 0.37; P = .002) and liver function (P = .001).

Study details: This retrospective, single-center study reviewed data on 1,173 adult patients with HBV-related HCC who had undergone liver resection and were initially treated with either TDF or ETV for chronic HBV infection.

Disclosures: The study was funded by Sun Yat-sen University Cancer Center physician-scientist funding and National Science and Technology Major Project of China. The authors reported having no conflict of interests.

Source: Wang XH et al. Tenofovir vs. entecavir on prognosis of hepatitis B virus-related hepatocellular carcinoma after curative resection. J Gastroenterol. 2022;57:185-198 (Feb 13). Doi: 10.1007/s00535-022-01855-x

Key clinical point: Patients receiving tenofovir disoproxil fumarate (TDF) vs. entecavir (ETV) after curative liver resection for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) showed significantly better overall survival and protection of liver function but no significant difference in the cumulative incidences of HCC recurrence.

Major finding: Although patients receiving TDF vs. ETV showed no significant difference in recurrence-free survival after propensity-score matching (hazard ratio [HR] 0.91; P = .45), they had significantly better overall survival (HR 0.37; P = .002) and liver function (P = .001).

Study details: This retrospective, single-center study reviewed data on 1,173 adult patients with HBV-related HCC who had undergone liver resection and were initially treated with either TDF or ETV for chronic HBV infection.

Disclosures: The study was funded by Sun Yat-sen University Cancer Center physician-scientist funding and National Science and Technology Major Project of China. The authors reported having no conflict of interests.

Source: Wang XH et al. Tenofovir vs. entecavir on prognosis of hepatitis B virus-related hepatocellular carcinoma after curative resection. J Gastroenterol. 2022;57:185-198 (Feb 13). Doi: 10.1007/s00535-022-01855-x

Screening for conditions like lung cancer has the potential to save lives, but can also lead to diagnoses that have little clinical impact. Such overdiagnosis was illustrated in a recent study from JAMA Internal Medicine of women in Taiwan who were screened for lung cancer using low-dose CT (LDCT).

The study, and the accompanying editorial, pointed out the potential for large databases of routine clinical data to track long-term outcomes, and potentially identify patient subgroups that could benefit from early diagnosis using digital technologies.

The Taiwanese findings echo a similar trend identified in a 2018 post hoc analysis of the Danish Lung Cancer Screening Trial, which estimated that 67.2% of cancers found during that CT screening program for current or former smokers were overdiagnosed. The authors recommended that researchers report rates of overdiagnosis in future screening studies.

The authors of the Taiwan study noted that LDCT is low cost and is frequently offered to individuals who are not considered at high risk of lung cancer, and advertisements in Taiwan often target women, who rarely smoke. The researchers examined data from the Taiwan National Cancer Registry. They looked for evidence of an increased incidence of early-stage detection and reduced incidence of late-stage diagnosis. They found that, from 2004 to 2018, there was an increase of lung cancer incidence from 2.3 to 14.4 per 100,000 (difference, 12.1; 95% confidence interval, 11.3-12.8), but no significant difference in the incidence of late-stage disease (from 18.7 to 19.3 per 100,000; difference, 0.6; 95% CI, –0.5 to 1.7).

“This combination of findings, an additional 12.1 early-stage cancers per 100,000 population and no reduction in late-stage cancers, is strongly suggestive of overdiagnosis,” the authors wrote.

It can be difficult to convince people of the potential harms of overdiagnosis, especially when patients have a nodule removed and remain healthy years later. “It’s very counterintuitive, but it’s a reality, and I think this paper paints the reality very, very clearly,” said Daniel Capurro, MD, PhD, deputy director of the Centre for the Digital Transformation of Health at University of Melbourne, and an author of the editorial.

The issue is that some lung cancers progress so slowly that they may never cause a problem clinically, and their removal can lead to unnecessary cost and risk. And it’s not just cancer. “There are a bunch of other conditions that are defined by specific criteria, but we don’t add the prognosis to that definition. At the individual patient level, we don’t know the prognosis,” Dr. Capurro said.

Dr. Capurro discussed the increasing use of digital technologies like smartphone apps. Machine learning can potentially use such data to diagnose conditions like sleep or mood disorders before they become clinically significant, allowing earlier intervention, but they could also lead to overdiagnosis. Dr. Capurro proposed using longitudinal databases to track patient outcomes, which could be applied to digital screening technologies.

“You might be able to find unknown patterns that help discriminate between these pathological definitions. You should be able to train (digital screens) with the pathological definition plus the disease trajectory as a way to improve that label,” he said.

The study was funded by the Taiwan Ministry of Health and Welfare Clinical Trial Center.

Screening for conditions like lung cancer has the potential to save lives, but can also lead to diagnoses that have little clinical impact. Such overdiagnosis was illustrated in a recent study from JAMA Internal Medicine of women in Taiwan who were screened for lung cancer using low-dose CT (LDCT).

The study, and the accompanying editorial, pointed out the potential for large databases of routine clinical data to track long-term outcomes, and potentially identify patient subgroups that could benefit from early diagnosis using digital technologies.

The Taiwanese findings echo a similar trend identified in a 2018 post hoc analysis of the Danish Lung Cancer Screening Trial, which estimated that 67.2% of cancers found during that CT screening program for current or former smokers were overdiagnosed. The authors recommended that researchers report rates of overdiagnosis in future screening studies.

The authors of the Taiwan study noted that LDCT is low cost and is frequently offered to individuals who are not considered at high risk of lung cancer, and advertisements in Taiwan often target women, who rarely smoke. The researchers examined data from the Taiwan National Cancer Registry. They looked for evidence of an increased incidence of early-stage detection and reduced incidence of late-stage diagnosis. They found that, from 2004 to 2018, there was an increase of lung cancer incidence from 2.3 to 14.4 per 100,000 (difference, 12.1; 95% confidence interval, 11.3-12.8), but no significant difference in the incidence of late-stage disease (from 18.7 to 19.3 per 100,000; difference, 0.6; 95% CI, –0.5 to 1.7).

“This combination of findings, an additional 12.1 early-stage cancers per 100,000 population and no reduction in late-stage cancers, is strongly suggestive of overdiagnosis,” the authors wrote.

It can be difficult to convince people of the potential harms of overdiagnosis, especially when patients have a nodule removed and remain healthy years later. “It’s very counterintuitive, but it’s a reality, and I think this paper paints the reality very, very clearly,” said Daniel Capurro, MD, PhD, deputy director of the Centre for the Digital Transformation of Health at University of Melbourne, and an author of the editorial.

The issue is that some lung cancers progress so slowly that they may never cause a problem clinically, and their removal can lead to unnecessary cost and risk. And it’s not just cancer. “There are a bunch of other conditions that are defined by specific criteria, but we don’t add the prognosis to that definition. At the individual patient level, we don’t know the prognosis,” Dr. Capurro said.

Dr. Capurro discussed the increasing use of digital technologies like smartphone apps. Machine learning can potentially use such data to diagnose conditions like sleep or mood disorders before they become clinically significant, allowing earlier intervention, but they could also lead to overdiagnosis. Dr. Capurro proposed using longitudinal databases to track patient outcomes, which could be applied to digital screening technologies.

“You might be able to find unknown patterns that help discriminate between these pathological definitions. You should be able to train (digital screens) with the pathological definition plus the disease trajectory as a way to improve that label,” he said.

The study was funded by the Taiwan Ministry of Health and Welfare Clinical Trial Center.

Screening for conditions like lung cancer has the potential to save lives, but can also lead to diagnoses that have little clinical impact. Such overdiagnosis was illustrated in a recent study from JAMA Internal Medicine of women in Taiwan who were screened for lung cancer using low-dose CT (LDCT).

The study, and the accompanying editorial, pointed out the potential for large databases of routine clinical data to track long-term outcomes, and potentially identify patient subgroups that could benefit from early diagnosis using digital technologies.

The Taiwanese findings echo a similar trend identified in a 2018 post hoc analysis of the Danish Lung Cancer Screening Trial, which estimated that 67.2% of cancers found during that CT screening program for current or former smokers were overdiagnosed. The authors recommended that researchers report rates of overdiagnosis in future screening studies.

The authors of the Taiwan study noted that LDCT is low cost and is frequently offered to individuals who are not considered at high risk of lung cancer, and advertisements in Taiwan often target women, who rarely smoke. The researchers examined data from the Taiwan National Cancer Registry. They looked for evidence of an increased incidence of early-stage detection and reduced incidence of late-stage diagnosis. They found that, from 2004 to 2018, there was an increase of lung cancer incidence from 2.3 to 14.4 per 100,000 (difference, 12.1; 95% confidence interval, 11.3-12.8), but no significant difference in the incidence of late-stage disease (from 18.7 to 19.3 per 100,000; difference, 0.6; 95% CI, –0.5 to 1.7).

“This combination of findings, an additional 12.1 early-stage cancers per 100,000 population and no reduction in late-stage cancers, is strongly suggestive of overdiagnosis,” the authors wrote.

It can be difficult to convince people of the potential harms of overdiagnosis, especially when patients have a nodule removed and remain healthy years later. “It’s very counterintuitive, but it’s a reality, and I think this paper paints the reality very, very clearly,” said Daniel Capurro, MD, PhD, deputy director of the Centre for the Digital Transformation of Health at University of Melbourne, and an author of the editorial.

The issue is that some lung cancers progress so slowly that they may never cause a problem clinically, and their removal can lead to unnecessary cost and risk. And it’s not just cancer. “There are a bunch of other conditions that are defined by specific criteria, but we don’t add the prognosis to that definition. At the individual patient level, we don’t know the prognosis,” Dr. Capurro said.

Dr. Capurro discussed the increasing use of digital technologies like smartphone apps. Machine learning can potentially use such data to diagnose conditions like sleep or mood disorders before they become clinically significant, allowing earlier intervention, but they could also lead to overdiagnosis. Dr. Capurro proposed using longitudinal databases to track patient outcomes, which could be applied to digital screening technologies.

“You might be able to find unknown patterns that help discriminate between these pathological definitions. You should be able to train (digital screens) with the pathological definition plus the disease trajectory as a way to improve that label,” he said.

The study was funded by the Taiwan Ministry of Health and Welfare Clinical Trial Center.

Some myths never die. The idea of taking 10,000 steps a day is one of them. What started as a catchy marketing slogan has become a mantra for anyone promoting physical activity. But the 10,000-step target is arbitrary and ignores a fundamental truth of lifestyle medicine: When it comes to physical activity, anything is better than nothing.

It all began in 1965 when the Japanese company Yamasa Tokei began selling a new step-counter which they called manpo-kei (ten-thousand steps meter). They coupled the product launch with an ad campaign – “Let’s walk 10,000 steps a day!” – in a bid to encourage physical activity. The threshold was always somewhat arbitrary, but the idea of 10,000 steps cemented itself in the public consciousness from that point forward.

iStock/thinkstockphotos

A version of this article first appeared on Medscape.com.

Some myths never die. The idea of taking 10,000 steps a day is one of them. What started as a catchy marketing slogan has become a mantra for anyone promoting physical activity. But the 10,000-step target is arbitrary and ignores a fundamental truth of lifestyle medicine: When it comes to physical activity, anything is better than nothing.

It all began in 1965 when the Japanese company Yamasa Tokei began selling a new step-counter which they called manpo-kei (ten-thousand steps meter). They coupled the product launch with an ad campaign – “Let’s walk 10,000 steps a day!” – in a bid to encourage physical activity. The threshold was always somewhat arbitrary, but the idea of 10,000 steps cemented itself in the public consciousness from that point forward.

iStock/thinkstockphotos

A version of this article first appeared on Medscape.com.

Some myths never die. The idea of taking 10,000 steps a day is one of them. What started as a catchy marketing slogan has become a mantra for anyone promoting physical activity. But the 10,000-step target is arbitrary and ignores a fundamental truth of lifestyle medicine: When it comes to physical activity, anything is better than nothing.

It all began in 1965 when the Japanese company Yamasa Tokei began selling a new step-counter which they called manpo-kei (ten-thousand steps meter). They coupled the product launch with an ad campaign – “Let’s walk 10,000 steps a day!” – in a bid to encourage physical activity. The threshold was always somewhat arbitrary, but the idea of 10,000 steps cemented itself in the public consciousness from that point forward.

iStock/thinkstockphotos

A version of this article first appeared on Medscape.com.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.