Liver Shorts July 2020

KA Strauss et al. Hepatology 2020; 71: 1923-39. Crigler-Najjar Syndrome Type 1: Pathophysiology, Natural History, and Therapeutic Frontier. This chart review  provides long-term data on phototherapy for  CN1 (n=28) over 30 years, bilirubin metabolism, and results from 17 who underwent liver transplantation at a median age of 16 years.  Background: “In 1952, John Crigler and Victor Najjar described 7 infants from 3 families who developed intractable nonhemolytic jaundice within the first week of life.”  Disorder is due to deficiency of uridine 5′-diphosphate glucuronyltransferase (UGT1A1, OMIM 218800). The report’s Table 1 provides management guidelines. 12 (43%) of patients developed cholelithiasis (pigmented stones) which exacerbated hyperbilirubinemia and resulted in cholecystectomy.

H Dang et al. Hepatology 2020; 71: 1910-22.  This multinational consortium retrospective study reviewed 1676 patients with HCV-related HCC.  They found that in patients who achieved a sustained virological response (SVR) after direct-acting antiviral (DAA) therapy had a significantly higher 5-year survival: 88% vs 66%, P<0.001; after regression analysis, SVR was independently associated with a 63% lower risk of 5-year all-cause mortality.  My take (borrowed from authors) Patients with HCV and HCC who are eligible for HCC therapy should also be considered for DAA therapy.

M Noureddin et al. Hepatology 2020; 71: 1940-52.  This study, a nested case-control analysis, examined a subset from a large prospective cohort of >215,000 adults in Hawaii and California for diet associations with nonalcoholic fatty liver disease (NAFLD); the subset consisted of 2974 patients with NAFLD and 29,474 matched controls.  Key findings: Red meat, processed read meat, poultry and cholesterol consumption were positively associated with NAFLD while dietary fiber was inversely associated with risk. My take: While sugar/fructose intake has been a dietary concern for NALFD, this study indicates that decreasing meat/cholesterol consumption and increasing fiber consumption would be beneficial to reduce risk of NALFD and advanced liver disease.

Increasing Incidence of Hepatocellular Carcinoma in the U.S.

A recent study (DL White et al. Gastroenterol 2017; 152: 812-20) provide data showing a striking increase in the incidence of hepatocellular carcinoma (HCC). Using data from the US Cancer Statistics Registry which covers 97% of U.S. population, the authors found the following:

  • HCC incidence rose from 4.4 per 100,000 in 2000 to 6.7 per 100,000 in 2012
  • The annual rate of increase was 4.5% from 2000-2009, but then 0.7% annually from 2010-2012
  • The greatest increase occurred in 55-59 year olds (8.9% annually) and 60-64 year olds (6.4% annually)

The main HCC risk factors are HCV, HBV, and alcoholic liver disease, though obesity-associated HCC is emerging as an important risk factor as well.  The highest rates of HCC are seen in southern and western states, with Texas having the highest rates overall.  The high rate in Texas is in part due to the higher rates of HCC in Hispanics.

Overall, the authors indicate that the rising HCC rates are most closely tied to the peak HCV cohort (1945-65) and speculate that the arrival of direct-acting antivirals may help. At the same time, this HCV cohort is composed “disproportionately [of] minorities and of lower socioeconomic status” and may have less access to these advances in treatment.  Furthermore, in states like Texas which did not adopt Medicaid expansion as part of the Affordable Care Act, there are more uninsured patients who will be less likely to identify preceding risk factors for HCC.

My take: Perhaps in 20 years, we will see HCC incidence maps that are improving as HCV treatments become more widely available.  This presumes that other HCC risk factors, including obesity and alcohol, do not worsen significantly.

Related blog posts:

Liver Briefs Feb 2017

JB Schwimmer et al. Gastroenterol 2016; 151: 1141-54.  Using a double-masked trial with 169 children with NAFLD, the use of cysteamine bitartrate for 1 year did not reduce histologic activity scores, but did reduce liver aminotransferase levels.

NA Terrault et al. Gastroenterol 2016; 151: 1131-40. The authors collected data from 2099 participants in the HCV-TARGET study who mainly received ledpasvir-sofosbuvir (311 received therapy in combination with ribavirin).  The study included 25% blacks, 66% with genotype 1A, 41% with cirrhosis, 50% with prior treatment, and 30% who were receiving proton pump therapy.  Key finding: SVR12 rates varied from 95% to 97% based on duration of therapy.  Factors that predicted SVR12 included higher albumin (>3.5 g/dL), lower total bilirubin (<1.2), absence of cirrhosis, absence of proton pump inhibitor therapy.

KR Olson et al. NEJM 2017; 376: 268-78.  This case report of an 18 yo woman with acute liver failure provides a helpful review.  For Wilson’s disease, the article reviews rapid diagnostic criteria: “a screen that shows a ratio of alkaline phosphatase (IU per liter) to total bilirubin (mg per deciliter) of lower than 4.0 and then subsequently shows a ratio of aspartate aminotransferase (IU per liter) to alanine aminotransferase (IU per liter) of higher than 2.2 has been described as 100% sensitive and specific for the diagnosis of Wilson’s disease.”  Making this diagnosis quickly is crucial and allows these patients to be UNOS status 1A, “the only cause of acute liver faliure that allows a patient with preexisting liver disease to be listed as status 1A”

Among children older than 10 years of age, Wilson's disease accounted for 90% of metabolic disease.

Among children older than 10 years of age, Wilson’s disease accounted for 90% of metabolic disease.

Sirolimus and transplant mortality

A surprise to me was a recent study which identified sirolimus as a risk factor for increased mortality and graft loss in HCV-positive liver transplant patients (Liver Transpl 2012; 18: 1029-36, commentary 1003-1004).

Sirolimus mechanism of action: inhibits mammalian target of rapamycin (mTOR) which is a phosphoinositide 3-kinase which affects cell proliferation, angiogenesis, and immune function.  For transplant patients, sirolimus blocks interleukin-2-induced stimulation of T lymphocytes.

Black box warnings for sirolimus: FDA warns that sirolimus can increase risk of hepatic artery thrombosis, graft loss, and death with de novo sirolimus-based treatment.

What’s different about HCV transplants? HCV reinfection occurs immediately during liver transplantation and “unlike all other indications, graft survival and patient survival have not improved” (between 1991-2001).  HCV transplant survival continues to be 10-15% lower than non-HCV transplant survival.  Immunosuppression allows more rapid progression of HCV; this allows ~20% of recipients to develop cirrhosis within 5 years of transplantation.

The authors of the study analyzed 26,414 patients (12,589 with hepatitis C virus) from the Scientific Registry of Transplant Recipients (SRTR) database; all recipients were >18 years.  Among this database, 1685 liver transplant recipients received sirolimus; in the majority, it was administered along with a calcineurin inhibitor.  A multivariate analysis of patient mortality showed the following were risk factors for increased mortality:

  • recipient age
  • donor age
  • hepatocellular carcinoma
  • diabetes
  • creatinine

Tacrolimus-based immunosuppression was associated with superior survival. Whereas, the use of sirolimus was associated with increased mortality in patients with HCV, even when adjusting for confounding variables (eg. renal function, and cancer).  In patients who received sirolimus at baseline, the adjusted HR for mortality at 3 years was 1.29 (p=0.0053).  In non-HCV patients, the adjusted HR for the sirolimus group was 1.09  (p=0.40).  Also, duration of exposure to sirolimus was directly correlated with worse outcomes.  Why?

This is not clear.  It is recognized that the study has several limitations.  Due to the nature of the SRTR database, there is not adequate information on how sirolimus may have affected viral load, histologic progression or causes of death.  Despite attempts to control for risk factors, it is possible that the sirolimus group did have higher disease severity.  Nevertheless, sirolimus effects on multiple cellular functions may have deleterious consequences in certain subsets of patients.

Effects of pegylated interferon on growth

Besides examining the effectiveness of pegylated interferon for hepatitis C virus (HCV) in children, the PEDS-C (Pediatric Study of Hepatitis C) trial data has been studied to determine the effects of pegylated interferon (PEG) on growth and body composition (Hepatology 2012; 56: 523-31).

In this study of 114 children who were treated with PEG along with ribavirin (RBV), anthropometric measurements, dual-energy X-ray absorptiometry, dietary intakes, and activity assessments were performed.  Of the initial 114 children (5-18 years), 107 received treatment for more than 24 weeks: 14 for 24 weeks, 82 for 48 weeks, and 11 for 72 weeks.

In the group treated for 48 weeks, 29 (33%) had more than a 0.5 unit decrement in height-for-age score (HAZ).  Based on figure 2 in the study, most of the HAZ decrement at 48 weeks and resolved at 144 weeks (time after treatment initiation).  In contrast, weight-for-age and BMI scores returned to baseline after stopping HCV therapy.  The authors note that while most growth parameters generally were “reversible with cessation of therapy…HAZ scores had not returned to baseline after 2 years of observation in many.”

Another observation from the study was that weight and height decreased in tandem.  In contrast to sequential change, this type of change indicates that other mechanisms besides poor intake are likely affecting linear growth.  These HAZ effects were noted in adolescents; there was no difference in HAZ scores in preadolescent patients.

The potential effects on growth may influence the timing of therapy.  At the same time, as new HCV treatments are studied in pediatric patients, the effects of interferon may become a moot point.

Related blog entries

Pediatric HCV Guidelines

Understanding IL28B

Increased ferritin predicts poor response in Hepatitis C

Unknown unknowns for Hepatitis C

Unknown unknowns for Hepatitis C

[T]here are known knowns; there are things we know that we know.
There are known unknowns; that is to say there are things that, we now know we don’t know.
But there are also unknown unknowns – there are things we do not know, we don’t know.
United States Secretary of DefenseDonald Rumsfeld February 2002

Reading a recent epidemiology article reminded me of the preceding referenced quote  (Hepatology 2012; 55: 1652-61).  This study took a close look at knowledge of being infected with hepatitis C virus (HCV) and what HCV infection may indicate.

The study identified 30,140 participants through the National Health and Nutrition Examination Survey (NHANES) conducted from 2001-2008.  The Centers for Disease Control (CDC) obtains nationally representative data on the health and nutritional status of noninstitutionalized civilians across the U.S.  NHANES uses a ‘complex, stratified, and mulitstage probability sampling design and collects information from approximately 5,000 persons per year using standardized household interviews, physical examinations, and testing of biologic samples.’

Participants 6 years of age or older who tested positive for anti-HCV antibodies were sent a report.  Out of the 30,140 participants, 393 (1.4%) had evidence of past or current HCV infection; 170 were available for the study investigators.  Only 49.7% were aware of HCV status prior to receiving NHANES letter.  Furthermore, only 3.7% were first tested for HCV because they or their doctor thought they were at risk for infection; most were tested as part of a routine exam (perhaps detected after elevated ALT values) (46.7%), due to symptoms (15.9%), or blood donation (9.7%).

Another aspect of the study was determining the participants’ understanding of HCV infection.  Correct responses to the HCV survey were more likely in individuals between 40-59 years of age, white non-Hispanics, and patients who had seen a doctor about their HCV infection.  Specific questions often answered incorrectly included the following:

  • whether HCV could be contacted by kissing –only 68% knew this was false
  • whether HCV could be transmitted sexually –only 64% knew this was true
  • whether HCV could be acquired during birth if mother had HCV –only 57% knew this was true

Take home points:

  • Risk-based screening for HCV will continue to fail.  Physicians may not elicit adequate information and patients may deny risky behaviors even if asked.
  • Approximately half of patients in this cohort were unaware of HCV infection.
  • Many misconceptions about HCV persist even among those who had received counseling.

Related blog posts:

Pediatric HCV Guidelines

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Additional resource:

http://www.cdc.gov/hepatitis/RiskAssessment/  This website allows individuals to assess their risk for hepatitis.

Increased ferritin predicts poor response in Hepatitis C

Serum ferritin levels were independently shown to be a risk factor for poor response to treatment in hepatitis C virus (HCV) infection (Hepatology 2012; 55: 1038-47).  This article adds additional information to previous work which has shown that increased iron can be a comorbid factor in chronic viral hepatitis and other liver diseases.

This study used the Swiss Hepatitis C Cohort Study (SCCS) (n=3648).  In this group, the success of treatment with pegylated interferon alpha and ribavirin were correlated with clinical and histological features.

Ferritin levels ≥ the sex-specific median values was one of the strongest pretreatment predictors of treatment failure (OR 0.45). It had a similar predictive effect as the IL28B genotype.  In addition, higher ferritin levels were associated with severe liver fibrosis (OR 2.67) and steatosis (OR 2.29).  For women the sex-specific median for ferritin level was 85 μg/L and for men it was 203 μg/L.  The authors note that these cutoffs are quite close to the upper limits of normal of the general population (150 and 300 respectively).

Mechanistically, HCV interferes with the host’s iron metabolism leading to iron accumulation in the liver.  Part of this is explained by down-regulation of hepcidin (Help with hepcidin).  Part is due to ferritin acting as an acute phase reactant to inflammation.  Ultimately, excess iron promotes liver inflammation, oxidative stress and mitochondrial dysfunction.

How important ferritin will be with newer therapies is not clear.  It is likely that patients that are less responsive to dual therapy (pegylated interferon/ribavirin) will have poorer response as well to triple or quadruple therapies.

Additional references/previous related posts:

Curing Hepatitis C without interferon

In the face of increasing morbidity and mortality, better therapies for Hepatitis C have emerged which if applied broadly have an opportunity to change the outcome.  Recently, several articles have highlighted the possibility of treating individuals without interferon.

  • Lok et al. NEJM 2012; 366: 216-224
  • Chayam et al. Hepatology 2012; 55: 742-48
  • Zeuzem et al. Hepatology 2012; 55: 749-58.

In the Lok study, 21 null responders (patients who failed to achieve ≥2log10 decline in HCV RNA after ≥12 weeks of peginterferon and ribavirin) were divided into two groups. In Group A, 36% of patients were able to achieve SVR12 using a combination direct-acting antivirals (DAAs) with non-overlapping resistance profiles — without the use of interferon. Group A patients received BMS-790052 (an oral, first-in-class, NS5A replication complex inhibitor) and BMS-650032 (an oral NS3 protease inhibitor). In Group B which included peginterferon and ribavirin the SVR12 was 100%. There were no serious adverse events, or discontinuations.  The most common side effects were diarrhea, fatigue, headache, and nausea.

In the Chayam study, the combination of BMS-790052 (now called daclatasvir) and BMS-650032 (now called asunaprevir) examined this combination of DAAs in null HCV responders with genotype 1B (in Japan).  Ten patients received both drugs for 24 weeks. All nine who completed treatment had an SVR.  One patient stopped the medication due to elevated bilirubin and lymphopenia which occurred following an apparent infectious gastroenteritis.

In the Zeuzem study, tegobuvir (a nonnucleoside polymerase inhibitor) and GS 9256 (an NS3 serine protease inhibitor) with RBV (n=15), with PEG/RBV (n=15) and without ribavirin (n=16) were administered in three arms for 4 weeks, followed by dual therapy with PEG and RBV.  The primary end point was rapid virologic response (RVR), defined as HCV RNA <25 IU/mL.  Reductions (mean) for HCV RNA were -4.1 log10 IU/mL for dual therapy, -5.1 log10 IU/mL for triple therapy, and -5.7 log10 IU/mL for quadruple therapy.  RVR was noted in 7% of dual Rx, 38% of triple therapy, and 100% of quadruple therapy.

These studies indicate that even for difficult to treat HCV patients that new oral medications are on the horizon that will increase cure rates and may allow effective regimens that do not include interferon.  This is good news because until recently regimens with interferon were more likely to provoke adverse reactions that to guarantee a cure.

Links to relevant blog entries on HCV:

HCV now more deadly than HIV

The cost of progress in treating Hepatitis C

Looking for trouble

Another life-threatening complication of HCV

Epidemiological studies have shown a causal relationship between B-cell non-Hodgkin lymphoma (B-NHL) and hepatitis C virus (HCV) (Hepatology 2012; 55: 634-641).  This is not simply an association but a cause and effect.

The cited reference reviews several aspects of this relationship including the mechanisms of lymphoproliferation, the epidemiology, the clinical manifestations, the treatment, the prognosis, and preventive measures.

  • With regard to epidemiology, the odds ratios are between 2.4 and 5.2.  This is a small risk compared to hepatocellular carcinoma.
  • Management: Lymphoma may regress with HCV treatment, indicating a role for HCV in pathogenesis.   HCV treatment may prevent the occurrence of B-NHLs as well.  For aggressive lymphomas, patients require systemic treatment with rituximab-based regimens (1st line treatment).
B-NHLs are not nearly as important as cirrhosis and hepatocellular carcinoma in terms of mortality and morbidity in patients with HCV.  It is nevertheless quite significant considering the number of infected persons worldwide.
Other related posts on HCV:

Additional references:

  • -Gastroenterology 2011; 140: 1182. Increasing HCC/Cirrhosis in HCV pts.
  • -Clinical Gastro & Hep 2008; 6: 451. HCV associated with increased risk of non-Hodgkins lymphoma. OR was 1.8 among n=4784 cases of NHL/n=6269 controls
  • -Clinical Gastro & Hep 2008; 6: 459. Overweight & obesity increase risk of HCC. n=1431 chronic HCV patients; 36% developed HCC over 10 year f/u. OR 1.9 of HCC if overweight & 3.1 OR of HCC if obese.
  • -NEJM 2002; 347: 89-95. regression of splenic lymphoma w HCV treatment.

HCV now more deadly than HIV

Hepatitis C virus (HCV) now kills more people in the United States than HIV (Ann Intern Med 2012; 156: 271-78).  Data from the CDC followed the mortality burden of Hepatitis B (HBV), HCV, and HIV from 1999 to 2007.    The data were derived from death certificates & a limitation was that these are often completed by individuals other than the primary physician.  Sometimes the exact cause is difficult to discern.  However, this is more likely to result in underreports of deaths from viral hepatitis compared with those from HIV.

In total, 21.8 million death certificates were analyzed.

  • HBV death rate stayed relatively constant –in 2007: 1815 deaths*
  • HCV death rate increased steadily –in 2007: 15106 deaths*
  • HIV death rate improved –in 2007: 12734 deaths*

*When infection was cause or underlying contributor of death

One in 33 baby boomers are infected with HCV; most do not know they are infected.  Three-fourths of the deaths for HCV are in this age group as well.  In addition, it is expected that mortality from HCV will grow over the next 10-15 years without a major intervention. http://www.ajc.com/health/hepatitis-c-deaths-up-1356460.html

Given the increasing HCV disease burden, this strengthens the rationale for more aggressive case finding and the use of more effective & more expensive therapies (see previous blog: The cost of progress in treating Hepatitis C.  Among patients with HCV with advanced disease/cirrhosis, monitoring for HCC is important (Looking for trouble).

Additional references:

  • -Hepatology 2011; 54: 1547. Excess mortality (6x gen population) in those who achieve SVR
  • -Gastroenterology 2010; 138: 513. Predicts peak cirrhosis due to HCV in year 2020; peak HCV prevalence was year 2000.
  • -Clin Gastro Hep 2010; 8: 924. Epidemiology 2010.
  • -Hepatology 2010; 52: 1543. Visceral adiposity is associated with increased histological findings and higher viral loads.
  • -Gastroenterology 2010; 138: 136. Predicting clinical outcomes: plt<99, Alb <3.5, AST/ALT ratio >1.2, & TB>2 all assoc with 40-50% risk of developing ‘clinical outcome’ in next 3.5yrs. Outcomes: ascites, variceal hemorrhage, decompensation according to CTP (66%), peritonitis, death (2%), encephalopathy
  • -Hepatology 2009; 49: 729. 5-yr f/u after successful HCV RX, n=150. 2 developed HCC.
  • -Gastroenterology 2009; 136: 138, 39(ed). HCC occurring c HCV ~1%/yr in HALT-C study. prolonged Rx -not helpful. n=1005
  • -Hepatology 2008; 47: 1128. Increasing mortality of HCV between 1995-2004. Due to aging of infected individuals.
  • -Hepatology 2008; 47: 1371. Genotype 4 review.
  • -Hepatology 2008; 47: 836. 2/121 bx of children had cirrhosis.
  • -J Pediatr 2007; 150: 168. n=60. Looked at two populations: look back after transfusion and referrals. mean age at infection 7 months, mean time with infection 13yrs. 12% developed significant fibrosis.
  • -Hepatology 2007; 45: 1076. Large study: Lancet 2006; 368: 938. 39,109 c HBV, 75,834 c HCV, 2,604 c both. death rate: 3.2%, 5.3%, 7.1% respecively. Increased rate of dying c HCV due to drug use rather than liver dz.
  • -Clin Gastro & Hep 2006; 4: 1190-1191, 1271-78, 1278-1282. slow progression of HCV in 184 untreated women infected in 1977 (mean 27 years) — 2.1% developed cirrhosis. genotype 1B ALT values correlated with change in histology.
  • -JPGN 2006; 43: 209. Review of 91 cases; 7 c cirrhosis at presentation (mean 11.7yrs)
  • -Clin Gastro & Hep 2005; 3: 910. cirrhosis in 71% after 60 years in Asian patients; 25% in Caucasian pts 61-80 who presumably had disease for shorter interval.
  • -Gastroenterology 2003; 125: 1695. obesity/insulin resistance worsens fibrosis in HCV
  • -Gastroenterology 2002; 123: 483-491. IFN Rx improved survival; n=2889. retrospective study.
  • -JPGN 2001;33: 22A. spontaneous clearance in 30% during short f/u; n=145.
  • -Hepatology 2000; 32: 91-96. Low likelihood of progression in cohort followed for 20yrs.