Category Archives: Hepatology

Treats (Tips) and Tricks for Using IBD Drugs in Patients with Hepatobiliary Comorbidities

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S Massironi et al. Inflamm Bowel Dis 2023; 29: 1477-1487. Use of IBD Drugs in Patients With Hepatobiliary Comorbidities: Tips and Tricks

This review article makes a number of useful points:

  • Almost all of the IBD medications (Anti-TNF, Vedolizumab, Ustekinumab, Tofacitinib, Ozanimod) should not be used in patients with untreated hepatitis B surface antigen positivity. Antiviral prophylaxis is recommended even patients with inactive disease (HBV DNA <2000 IU/mL/normal ALT) starting 2 weeks prior to immunosuppression up to 12 weeks after immunosuppression discontinuation.
  • Anti-TNF, Vedolizumab, and Ustekinumab can be safely used in patients with cirrhosis, tofacitinib requires a dose reduction, and ozanimod is NOT recommended
  • Autoimmune hepatitis may be triggered (rarely) by use of anti-TNFs; however, these agents have been uses off-label as a rescue therapy for AIH as well.
  • Anti-TNFs do not appear worsen liver function in PSC and may be associated with improvement in MASH (NASH)
  • Drug-induced liver injury (DILI) is common with anti-TNFs, often seen between the second and fifth doses. It is “generally transient and asymptomatic.” DILI may occur with ustekinumab, tofacitinib and ozanimod.
  • Tofacitinib may have a favorable effect on PSC. A retrospective study with 5 patients reported a 28% and 39% decrease respectively in total bilirubin and alkaline phosphatase within 6 months of starting therapy, A separate study with 42 patients showed a non-significant drop in alkaline phosphatase from 150 U/L to 132 U/L at 12 month followup.
  • The authors note that in patients with cirrhosis and posttransplantation, “vedolizumab and ustekinumab should be preferred due to their safer profile linked to infectious risk.”
  • “Patients with hepatobiliary disorders are often excluded from pivotal trials.” This contributes to a significant knowledge gap for patients with these comorbid conditions which are frequent in patients with IBD

My take: I don’t think I will be too popular if I hand out copies of this article to the kids I see later today –despite the useful advice. (This post was meant to be published on Halloween)

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Hepatitis C is Undertreated in the U.S.

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C Wester et al. MMWR 2023; 72 (26): 716-720. Open Access! Hepatitis C Virus Clearance Cascade — United States, 2013–2022 (starts on page 16 of PDF)

Key findings:

  • Among the approximately 1.0 million persons in this analysis with initial infection, only 34% had laboratory evidence of viral clearance
  • Overall, viral clearance was lowest among persons aged 20–39 years (24%). Patients 0-19 were not included in this analysis
  • To overcome the low cure rate, some have recommended a subscription model for HCV treatment; this was piloted in Louisiana. In this pilot, the state paid a lump sum to make the drug available for free to all patients on Medicaid and federal prisoners. Francis Collins has indicated that a national program, while expensive, would save the government $13 billion in 10 years (Source: Infectious Disease Special Edition, 6/30/23: Most Americans With HCV Not Receiving DAAs)

My take: Improving access to HCV treatment has the potential to save livers, save lives and save money.

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Gene Therapy for Crigler-Najjar

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L D’Antiga et al. NEJM; 2023; 389: 620-631. Gene Therapy in Patients with the Crigler–Najjar Syndrome

Methods: Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 μmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy. The infusion protocol included administration of sirolimus adjusted for a trough of 4-12 mcg/L (starting 1 week prior to infusion) and steroids (IV day prior then oral for 8 weeks). .

Key findings

  •  By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 μmol per liter.
  • The patients who received the higher dose had bilirubin levels below 300 μmol per liter in the absence of phototherapy at the end of follow-up; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], was149±33 μmol per liter.
  • No serious adverse events were reported. Mild increase in ALT levels were seen in 4 of 5 patients; this was “potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids.”
This figure shows the response of the serum bilirubin in patients receiving the higher dose of the infusion.

My take: This study shows that the GNT0003 increased UGT1A1 activity to levels that permitted cessation of phototherapy; this persisted for 18 months after treatment. Further studies are needed.

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Why Carvedilol Is Considered Best Pharmaceutical Agent to Prevent Variceal Bleeding (in Adults)

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M Jachs et al. Clin Gastroenterol Hepatol 2023; 21: 2318-2326. Open Access! Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis

Associated editorial: J Bosch. Clin Gastroenterol Hepatol 2023; 21:2195-2196. Open Access! Carvedilol as Best β-Blocker for Secondary Prophylaxis of Variceal Bleeding: Are We There, or Not Yet?

Key findings:

  • In a retrospective cohort comprising 87 adult patients receiving NSBB (non-selective beta blocker) in addition to band ligation after variceal bleeding, carvedilol induced more profound decreases in hepatic venous pressure gradient compared with propranolol. The higher rate of chronic hepatic venous pressure gradient response to carvedilol (53.3% vs 28.6%; P = .034) was paralleled by lower rates of variceal rebleeding, liver-related death, and further nonbleeding decompensation.

In the discussion and the editorial, it is noted that there is high-quality evidence that carvediol is superior for primary variceal prophylaxis in adults. “Carvedilol increasingly is used for the prevention of variceal bleeding, 2 and, based on the recent landmark PREDESCI study, overall hepatic decompensation/ascites3 in compensated cirrhosis, because it induces HVPG response (a ≥10% decrease in HVPG is sufficient in primary prophylaxis17) in up to 75% of patients vs 50% when using propranolol. However, it induces more pronounced decreases in blood pressure, which may be detrimental in patients with (refractory) ascites.15“

Though there are concerns about dropping blood pressure, the editorial notes that “up to two-thirds of patients with compensated cirrhosis” have high blood pressure. The editorial concludes that “the study still strongly suggests that carvedilol is at least as safe as propranolol…. I am in complete agreement with the authors in suggesting that carvedilol is likely to represent the best NSBB in the treatment of portal hypertension regardless of the clinical scenario, including prevention of decompensation, ascites, first bleeding, or recurrent bleeding.” The author notes that the “recent Baveno VII recommendations declare carvedilol as the preferred NSBB, and support its use in all compensated patients with direct (HVPG ≥10 mm Hg) or indirect signs of clinically significant portal hypertension.”(J Hepatol. 2022; 76: 959-974. Baveno VII: renewing consensus in portal hypertension)

My take: In adults, Carvediol is the best NSBB for portal hypertension. In children, who may be more prone to hypotension, more data is needed.

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Juan-Les-Pins, France

FGF21 Analogue Pegozafermin in NASH (MASH)

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R Loomba et al. NEJM 2023; DOI: 10.1056/NEJMoa2304286. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH

Background: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia

Methods: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, 222 patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis were randomly assigned patients to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. 

Key findings:

  • The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group, 26% in the 30-mg pegozafermin group, and 27% in the 44-mg pegozafermin group
  •  The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group, 23% in the 30-mg pegozafermin group, and 26% in the 44-mg pegozafermin group
  • The most common adverse events associated with pegozafermin therapy were nausea and diarrhea.

My take: Thus far, there are no approved pharmacologic therapies for NASH, so this phase 2 study of pegozafermin is an important early step. It is likely that some of the medications which help obesity will likely help with NASH as well.

You No Longer Have Fatty Liver Disease-You Have Steatotic Liver Disease!

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A total of 236 panelists from 56 countries participated in four online surveys and two hybrid meetings.

Key points:

  • Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various “aetiologies” of steatosis.
  • The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors (see 2nd figure).
  • The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for NASH.
  • Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD.
  • A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350 g/week and 210 to 420 g/week for females and males respectively). 

AASLD News Digest: “MASLD, formerly known as NAFLD, is the most common chronic liver disease around the world, affecting more than 30% of global population. This was why it was vital that the global liver community coalesce around an affirmative, non-stigmatizing name and diagnosis. Ultimately, the global members of the Nomenclature Development Initiative were focused on ensuring the global community had better nomenclature that could be used around the world so that the research and funding could be better directed to save more people’s lives.”

My take: NAFLD is now MASLD –time to update patient handouts (hopefully someone at GIKids.org is on top of this). Aslo, if you have really bad disease, should it be called the ‘monster MASH’ ?

Favorable Phase II Study of Cilofexor for Patients with PSC

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M Trauner et al. Clin Gastroenterol Hepatol 2023; 21: 1552-1560. Open Access! Safety and Sustained Efficacy of the Farnesoid X Receptor (FXR) Agonist Cilofexor Over a 96-Week Open-label Extension in Patients With PSC

Study: There were 52 subjects enrolled in the phase II study, 47 (90%) continued in the open-label extension phase. Key findings:

  • At week 96, reductions in serum alkaline phosphatase (median, −8.3%), gamma-glutamyl transferase (−29.8%), alanine aminotransaminase (−29.8%), and aspartate aminotransaminase (−16.7%) occurred, and rebounded after 4 weeks of untreated follow-up. Serum cytokeratin 18 M30 and M65 (which are markers of apotopsis and necrosis)were also reduced in the OLE

My take (from authors): “Whether cilofexor impacts clinically relevant endpoints associated with PSC await the results from the placebo-controlled, phase III PRIMIS study.”

Longitudinal relative change in serum ALP, GGT, and ALT from OLE baseline to week 96
and then 4-week, untreated follow up (F/U).

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Liver Shorts: Relationship of Hepatic Steatosis to Cardiovascular Disease and the Cost of Liver Transplantation

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HS Ahmed et al. Hepatology 2023; 77: 2063-2072. The association between hepatic steatosis and incident cardiovascular disease, cancer, and all-cause mortality in a US multicohort study

The authors included 10,040 participants from the Framingham Heart Study, the Coronary Artery Risk Development in Young Adults Study, and the Multi-ethnic Study of Atherosclerosis to assess the longitudinal association between liver fat (defined on CT) and incident cardiovascular disease (CVD).

Key finding:

Hepatic steatosis was associated with all-cause mortality after 12.7 years of mean follow-up when adjusting for baseline CVD risk factors, including body mass index (HR: 1.21, 1.04–1.40); however, the association between hepatic steatosis and incident CVD was not statistically significant after we accounted for body mass index in models considering baseline covariates or time-varying covariates. We observed no association between hepatic steatosis and CVD-related mortality or incident cancer.

My take: While CVD is the leading cause of mortality in patients with fatty liver disease, this study suggests that hepatic steatosis is a marker for this increased risk rather than an independent cause.

DU Lee et al. Liver Transplantation 2023; 29: 626-643. The trends in cost associated with liver transplantation in the US: Analysis of weighted hospital data

This lengthy article is loaded with data on trends and costs of liver transplantation in the U.S.

Key findings:

  • From 2016 to 2019, the estimated total number of LT-related hospitalizations in the US were 6685, 7075, 7260, and 7815 cases respectively.
  • There was a general increase in the total cost of LT-related hospitalizations over the years: $945.75, $1010.23, $1052.46, and $1143.84 in millions of dollars.

Editorial: A Kaplan et al. Liver Transplantation 2023; 29: 568-569. Open Access!
Liver transplant at all costs Key points:

  • Mean costs per patient for transplant-related hospitalization were around $145,000.
  • “Lee and colleagues’ important study adds to the growing concern over rising costs for LT. However, LT is 1 of many fields that must utilize a scarce resource for the maximal benefit of society. Balancing costs with a life-saving procedure that is very expensive will continue to be a persistent challenge.”

My take: It is likely that the costs of liver transplantation are going to continue to rise unless we develop a shortage of suitable liver donors or a shortage of transplant personnel. Severe fatty liver disease and alcoholic liver disease continue to increase in frequency while hospital costs continue to soar. Reducing costs will rely on reversing the tide of these diseases.

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Watersound, FL

Fatty Liver Disease AASLD Practice Guidance 2023

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ME Rinella et al. Hepatology 2023; 77: 1797-1835. Open Access! AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease

This 38 page report has a ton of updated recommendations and useful advice –geared to adults with fatty liver disease. The last ~dozen pages are the 491 references.

Some of the useful points:

  • CVD and nonhepatic malignancies are the most common causes of mortality in patients with NAFLD without advanced fibrosis; death from liver disease predominates in patients with advanced fibrosis.
  • Initial lab evaluation in adults:
  • Statins are safe and recommended for CVD risk reduction in patients with NAFLD across the disease spectrum, including compensated cirrhosis.
  • Patients with NAFLD should be screened for the presence of T2DM. T2DM is the most impactful risk factor for the development of NAFLD, fibrosis progression, and HCC.108–111 Given the central pathogenic role that insulin resistance plays in the pathogenesis of both T2DM and NAFLD, it is not surprising that patients with T2DM have a higher prevalence of NAFLD (ranging from 30% to 75%)10,112,113 and a higher risk of developing NASH with fibrosis.93,114–117 
  • Other important comorbidities: dyslipidemia, obstructive sleep apnea, cardiovascular disease, and chronic kidney disease

Lifestyle factors that can be beneficial:

  • Table 6 lists potential medications though there are no FDA approved treatments for fatty liver disease. Bariatric surgery is also a beneficial treatment option “in patients who meet criteria for metabolic weight loss surgery, as it effectively resolves NAFLD or NASH in the majority of patients without cirrhosis and reduces mortality from CVD and malignancy.”
  • Potentially useful medications include Vitamin E, Pioglitazone, Liraglutide, Semaglutide, Tirzepatide and SGLT-2i. “Semaglutide can be considered for its approved indications (T2DM/obesity) in patients with NASH, as it confers a cardiovascular benefit and improves NASH. Pioglitazone improves NASH and can be considered for patients with NASH in the context of patients with T2DM . Available data on semaglutide, pioglitazone, and vitamin E do not demonstrate an antifibrotic benefit, and none has been carefully studied in patients with cirrhosis.”
  • Treatments NOT Recommended: “Metformin, ursodeoxycholic acid, dipeptidyl peptidase-4, statins, and silymarin are well studied in NASH and should not be used as a treatment for NASH as they do not offer a meaningful histological benefit.”

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How Obesity Permeates Transplant Medicine

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A Mathur. Liver Transplantation 2023; 29: 465-466. Open Access! Salvaging the fatty liver for transplant: is short duration NMP enough? (ed)

 “As of 2020, the Center for Disease Control (CDC) notes that 40% of the ~258 million US adults suffer from obesity. This represents just more than a 100 million people suffering from obesity. In addition, about 23 million people suffer from severe obesity with a body mass index >40 kg/m2.” Fatty liver disease (aka NAFLD), driven primarily by obesity, is a leading cause of liver transplantation. In addition, fatty liver disease is impacting the ability to treat liver failure.

“The end result of this epidemic is that we are identifying a greater proportion of organ donors with varying degrees of liver steatosis. Transplantation of steatotic livers is associated with an increased degree of ischemia-reperfusion injury (IRI) and release of inflammatory cytokines from the graft. The consequences of this can range from severe reperfusion syndromes with immediate vasoplegia and circulatory collapse to distant organ dysfunction with acute kidney injury, liver allograft dysfunction, and primary nonfunction (PNF).”

In order to try to identify suitable liver organs for transplantation, researchers are trying to identify strategies to utilize steatotic grafts safely. Patrono et al (Liver Transplantation 2023; 29: 508-502) examined the feasibility of using normothermic machine perfusion (NMP) in the setting of macrovesicular steatosis (MaS) ≥30%. They identified 10 patients who had liver transplants using NMP in patients with MaS ≥30%; 4 additional organs were not used despite NMP. 8 of 10 patients showed good liver function, representing 57% (8 of 14) of NMP fatty organs.

Another study in the same issue (NB Ha et al. Liver Transplantation 2023; 29: 476-484) showed that patients with sarcopenic obesity (=low muscle mass obesity) had high waitlist mortality of 40% compared to 21% and 12% for those with sarcopenia without obesity and for those with obesity without sarcopenia, respectively.

My take: Obesity increases the risk of fatty liver associated cirrhosis/liver failure, and is impacting the availability of suitable organs for those in need. Furthermore, in those with obesity, the presence of sarcopenia increases the risk of death on transplant waitlist.

Tucson Botanical Gardens