ALCOHOLIC HEPATITIS

BY KEMBOI KIBET

  • Alcoholic liver disease (ALD) encompasses a spectrum of injury, ranging from simple steatosis to frank cirrhosis.
  • Alcohol remains amajor cause of liver disease worldwide
  • It is common for patients with ALD to share risk factors for simultaneous injury from other liver insults (e.g., coexisting nonalcoholic fatty liver disease, or chronic viral hepatitis).
  • The spectrum of alcohol-related liver injury varies from simple steatosis to cirrhosis.
  • These are not necessarily distinct stages of evolution of the disease, but rather, multiple stages that maybe present simultaneously in a given individual.
  • These are oft en grouped into three histological stages of ALD, including
    • fatty liver or simple steatosis.
    • alcoholic hepatitis (AH).
    • chronic hepatitis with hepatic fibrosis or cirrhosis.
  • The latter stages may also be associated with a number of histological changes, including
    • Mallory’s hyaline
    • megamitochondria
    • perivenular and perisinusoidal fibrosis
  • Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol.
  • Alcoholic hepatitis (AH) remains a common and life threatening cause of liver failure, especially when it is severe.
  • Although the term “acute” is frequently used to describe this form of liver injury, it is usually subacute and has been developing for weeks to months before it becomes clinically apparent.

ETIOLOGY

  • Patients with this form of alcoholic liver disease usually have a history of drinking heavily for many years.
  • Observational studies have shown an increased risk of cirrhosis with ingestion of greater than
    • 10-20 g of alcohol per day in women and
    • more than 20-40 g/d in men.

RISK FACTORS

  • A variety of genetic,environmental and gender-related factors appear to independently influence the development of alcoholic liver disease.
  • Age, female gender, excess body weight [body mass index (BMI) > 27 kg/m2 in men, BMI > 25 kg/m2 in women have been identified as independent risk factors for development of liver disease. (Bruguera 2014)
  • In addition to a smaller volume of distribution, women are at higher risk due to a relative deficiency of gastric alcohol dehydrogenase compared to men.
  • several women have developed AH after gastric bypass, in which the amount of gastric mucosa available to metabolize alcohol was reduced.
  • More severe forms of AH are associated with consumption of large amounts of alcohol or binge drinking.
  • Not surprisingly concomitant malnutrition and the presence of coexisting hepatitis C has also been linked to a poorer prognosis.(Leslie, Pawloski et al. 2014)
  • The combination of hepatitis C virus and alcohol predisposes to moreadvanced liver injury than alcohol alone,76,77 with disease at a younger age, more severe histological features, and a decreased survival.(Stimac, Bradaric et al. 2013)
  • The risk of developing cirrhosis increases with the ingestion of > 60-80 g/day of alcohol for 10 years or longer in men, and >20g/day in women.6,50 Yet, even drinking at these levels, only 6%-41% develop cirrhosis.

EIDEMIOLOGY

  • The true prevalence of alcoholic hepatitis, especially of its milder forms, is unknown, because patients may be asymptomatic and never seek medical attention.
  • In the United States alone, alcoholic liver disease affects more than 2 million people (ie, approximately 1% of the population).
  • Although the exact prevalence is unknown, approximately 7.4% of adult Americans were estimated to meet DSM-IV criteria for the diagnosis of alcohol abuse and/or alcohol dependence in 1994
  • More recent data suggest 4.65% meet criteria for alcohol abuse and 3.81% for alcohol dependence. In 2003, 44% of all deaths from liver disease were attributed to alcohol.
  • Racial differences in incidence – no genetic predilection is noted for any particular race
  • Alcoholic hepatitis can develop at any age. However, its prevalence parallels the prevalence of ethanol abuse in the population, with a peak incidence in individuals aged 20-60 years.
  • Sexual differences in incidence – Women develop alcoholic hepatitis after a shorter period and smaller amounts of alcohol abuse than men, and alcoholic hepatitis progresses more rapidly in women than in men.

PATHOGENESIS

Ethanol metabolism

  • Most tissues of the body, including the skeletal muscles, contain the necessary enzymes for the oxidative or nonoxidative metabolism of ethanol.
  • However, the major site of ethanol metabolism is the liver.
  • Within the liver, 3 enzyme systems metabolise ethanol—
  1. Cytosolic ADH uses nicotinamide adenine dinucleotide (NAD) as an oxidizing agent. ADH exists in numerous isoenzyme forms in the human liver and is encoded by 3 separate genes, designated as ADH1, ADH2, and ADH3. Variations in ADH isoforms may account for significant differences in ethanol elimination rates.
  2. The microsomal ethanol-oxidizing system (MEOS) uses nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen. The central enzyme of MEOS is cytochrome P-450 2E1 (CYP2E1).
  • Peroxisomal catalase uses hydrogen peroxide as an oxidizing agent.
  • The product of all 3 reactions is acetaldehyde, which is then further metabolized to acetate by acetaldehyde dehydrogenase (ALDH).
  • Acetaldehyde is a reactive metabolite that can produce injury in a variety of ways.
  1. Toxic effects on cell membranes
  • Ethanol and its metabolite, acetaldehyde damage liver cell membranes.
  • Ethanol can alter the fluidity of cell membranes, thereby altering the activity of membrane-bound enzymes and transport proteins.
  • Ethanol damage to mitochondrial membranes may be responsible for the giant mitochondria (megamitochondria) observed in patients with alcoholic hepatitis.
  • Acetaldehyde-modified proteins and lipids on the cell surface may behave as neoantigens and trigger immunologic injury.
  1. Hypermetabolic state of the hepatocyte
  • Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone 3) of the hepatic lobule.
  • This zone is known to be sensitive to hypoxic damage.
  • Ethanol induces a hypermetabolic state in the hepatocytes, partially because ethanol metabolism via MEOS does not result in energy capture via formation of ATP.
  • Rather, this pathway leads to loss of energy in the form of heat.
  • In some studies, antithyroid drugs, such as propylthiouracil (PTU), that reduce the basal metabolic rate of the liver have shown to be beneficial in the treatment of alcoholic hepatitis.
  1. Generation of free radicals and oxidative injury
  • Free radicals, superoxides and hydroperoxides, are generated as byproducts of ethanol metabolism via the microsomal and peroxisomal pathways.
  • In addition, acetaldehyde reacts with glutathione and depletes this key element of the hepatocytic defense against free radicals.
  • Other antioxidant defenses, including selenium, zinc, and vitamin E, are often reduced in individuals with alcoholism.
  • Peroxidation of membrane lipids accompanies alcoholic liver injury and may be involved in cell death and inflammation.
  1. Steatosis
  • Oxidation of ethanol requires conversion of NAD to the reduced form NADH.
  • Because NAD is required for the oxidation of fat, its depletion inhibits fatty acid oxidation, thus causing accumulation of fat within the hepatocytes (steatosis).
  • Some of the excess NADH may be reoxidized in the conversion of pyruvate to lactate.
  • Accumulation of fat in hepatocytes may occur within days of alcohol ingestion;
  • with abstinence from alcohol, the normal redox state is restored, the lipid is mobilized, and steatosis resolves.
  • Although steatosis has generally been considered a benign and reversible condition, rupture of lipid-laden hepatocytes may lead to focal inflammation, granuloma formation, and fibrosis, and it may contribute to progressive liver injury
  • Nonoxidative metabolism of ethanol may lead to the formation of fatty acid ethyl esters, which may also be implicated in the pathogenesis of alcohol-induced liver damage.
  1. Formation of acetaldehyde adducts
  • Acetaldehyde may be the principal mediator of alcoholic liver injury.
  • The deleterious effects of acetaldehyde include
    • impairment of the mitochondrial beta-oxidation of fatty acids,
    • formation of oxygen-derived free radicals,
    • depletion of mitochondrial glutathione.
  • In addition, acetaldehyde may bind covalently with several hepatic macromolecules, such as amines and thiols, in cell membranes, enzymes, and microtubules to form acetaldehyde adducts.
  • This binding may trigger an immune response through
    • formation of neoantigens,
    • impair function of intracellular transport through precipitation of intermediate filaments and other cytoskeletal elements,
    • stimulation of hepatic stellate cells to produce collagen.
  • ALDH is downregulated by long-term ethanol abuse, with resultant acetaldehyde accumulation.
  1. Role of the immune system
  • Active alcoholic hepatitis often persists for months after cessation of drinking.
  • Its severity may worsen during the first few weeks of abstinence.
  • This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury.
  • levels of serum immunoglobulins, especially the immunoglobulin A (IgA) class, are increased in persons with alcoholic hepatitis.
  • Antibodies directed against acetaldehyde-modified cytoskeletal proteins can be demonstrated in some individuals.
  • Autoantibodies, including antinuclear and anti–single-stranded or anti–double-stranded DNA antibodies, have also been detected in some patients with alcoholic liver disease.
  • B and T lymphocytes are noted in the portal and periportal areas, and natural killer lymphocytes are noted around hyalin-containing hepatocytes.
  • Peripheral lymphocyte counts are decreased with an associated increase in the ratio of helper cells to suppressor cells, signifying that lymphocytes are involved in a cell-mediated inflammatory process.
  • Lymphocyte activation upon exposure to liver extracts has been demonstrated in patients with alcoholic hepatitis.
  • Immunosuppressive therapy with glucocorticoids appears to improve survival and accelerate recovery in patients with severe alcoholic hepatitis.
  1. Cytokines
  • Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells. (Marra and Tacke 2014)
  • Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)–1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis. (Leake 2014)
  • Inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis
  1. Role of concomitant viral disease
  • Alcohol consumption may exacerbate injury caused by other pathogenic factors, including hepatitis viruses.
  • Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion.
  • Possible mechanisms include the impairment of immune-mediated viral killing or enhanced virus gene expression due to the interaction of alcohol and hepatitis C virus.

CLINICAL PRESENTATION

Questions to ask patients with suspected alcoholic hepatitis

  1. When did you first start to drink alcohol?
  2. How many days per week do you usually drink?
  • How many years have you been drinking on a regular or daily basis?
  1. How many times have you been arrested for driving under the
  2. influence of alcohol?
  3. How many times have you been arrested for public intoxication?
  • What type of alcohol do you usually drink? Beer? Wine? Hard liquor?
  • How many drinks of each type of alcohol do you drink on an average
  1. day?
  2. Do you usually drink at home? Bars?
  3. Have you been through an alcohol rehabilitation program? What typeinpatient
  • or outpatient? How many times?
  • Have there been prolonged times when you drank no alcohol?
  • When was your last drink?

HISTORY

  • patients with AH have been drinking heavily for years and then report a dramatic increase in the amount of alcohol intake, usually relating to a major life stressor, such as death of a parent, loss of a job, divorce etc
  • patients have often stopped drinking alcohol days to weeks prior to presentation due to
    • Malaise,
    • Poor appetite,
    • The realization that their drinking finally“caught up” with them.
  • Most commonly patients present with nonspecific complaints such as
    • Anorexia (27-77%)
    • Nausea and vomiting (34-55%)
    • Abdominal pain (27-46%)
    • Weight loss (29-43%)

PHYSICAL EXAMINATION

  • Physical Examination Findings
    • Hepatomegaly (71-81%)
    • Ascites (35%)
    • Encephalopathy (from asterixis to coma) (18-23%)
    • Gastrointestinal bleeding requiring transfusion (23%)
    • Jaundice (37-100%)
    • Malnutrition (56-90%)
    • Hepatic bruit

LABORATORY DATA

Laboratory findings in AH are often nonspecific, but can on occasion provide clues to the diagnosis. These include

Liver Function Test

  • Mild to moderately elevated transaminases,
  • Ast: alt ratio above 1.5 with
  • Ast greater than 45 u/l but < 300 u/l.
  • However, an unusual variant of AH, known as alcoholic foamy degeneration, can lead to an AST as high as 730 U/L.
  • A serum bilirubin >2 mg/dl is often required to make a diagnosis,
  • Alkaline phosphatase (ALP) level elevations are typically mild in persons with alcoholic hepatitis.
  • The gamma-glutamyl transpeptidase (GGT) level is elevated markedly by alcohol use. (Although a normal value helps to exclude alcohol as a cause of liver disease, an elevated level is of no value in distinguishing between simple alcoholism and alcoholic hepatitis.)
  • Total blood cholesterol levels < 100 mg/dl can predict poor outcome; the lower the cholesterol, the worse the prognosis.

CBC Count

  • A complete blood cell (CBC) count commonly reveals some degree of neutrophilic leukocytosis with bandemia.
  • Usually, this is moderate; however, rarely, it is severe enough to provide a leukemoid picture.
  • Moderate anemia may be observed.
  • Alcohol use characteristically produces a moderate increase in MCV
  • Thrombocytosis may be observed as part of the inflammatory response;
  • Conversely, myelosuppression or portal hypertension with splenic sequestration may produce thrombocytopenia.

Screening Blood Tests

  • Screening blood tests to exclude other conditions (appropriate in any patient with alcoholic hepatitis) may include the following:
    • Hepatitis B surface antigen (hbsag) detects hepatitis B
    • Anti–hepatitis C virus by enzyme-linked immunosorbent assay (ELISA) detects hepatitis C
    • Ferritin and transferrin saturation detect hemochromatosis
    • Marked elevation of aminotransferase levels should raise concern for viral hepatitis or drug hepatotoxicity; in particular, people who are alcoholics may develop severe liver necrosis from standard therapeutic doses of acetaminophen
    • Alpha-fetoprotein (AFP) levels – Rapid deterioration of liver function should raise the possibility of hepatocellular carcinoma (HCC)
    • Alkaline phosphatase (ALP) Jaundice with fever can be caused by gallstones producing cholangitis

Liver Biopsy

  • Liver biopsy is not always required in the evaluation of alcoholic hepatitis,
  • but it may be useful in establishing the diagnosis, in determining the presence or absence of cirrhosis, and in excluding other causes of liver disease.
  • The risk of performing the biopsy should be weighed against the risk associated with the probable course of therapy, or the possible risk of an investigational treatment.
  • Percutaneous liver biopsy – should be avoided in the presence of severe thrombocytopenia or coagulopathy because of the risk of serious (possibly fatal) hemorrhage.
  • Transjugular liver biopsy – the risk of hemorrhage should be reduced. It can determine the transhepatic venous pressure gradient.
  • In alcoholic hepatitis, injury is characteristically most prominent in centrilobular (perivenular) areas (zone 3 of Rappaport).
  • Hepatocytes exhibit ballooning with necrosis.
  • Focal accumulation of polymorphonuclear leukocytes is noted in areas of injury.
  • Lymphocytes may also be present, especially in portal tracts.
  • Ropy eosinophilic hyaline inclusions- Mallory bodies may be observed in the perinuclear cytoplasm.
  • With electron microscopy, Mallory bodies may be observed to be composed of fibril clumps that histochemically are identifiable as intermediate filaments.
  • Mallory bodies are characteristic of alcoholic hepatitis, but they are not always present in this disease, and, occasionally, they can be observed in a variety of other disorders.
  • Macrovesicular steatosis, perivenular fibrosis, and frank cirrhosis commonly coexist with alcoholic hepatitis.

Ultrasonography

  • provides a good evaluation of the liver and other viscera, and it permits guided liver biopsy.
  • the liver appears enlarged and diffusely hyperechoic.
  • Features suggestive of coexistent portal hypertension and/or cirrhosis include the presence of varices, splenomegaly, and ascites.
  • helpful in excluding gallstones, bile duct obstruction, and hepatic or biliary neoplasms.
  • if stones are found or fever persists, cholangiography may be necessary.
  • Rapid deterioration of liver function should raise the possibility of hepatocellular carcinoma, which can be tested for by ultrasonography, computed tomography [CT] scanning, magnetic resonance imaging [MRI]) of the liver.

TREATMENT

MANAGEMENT

  • Cessation of alcohol consumption is the single most important treatment; without this all other therapies are of limited value.
  • Abstinence is even effective at preventing progression of liver disease and death when cirrhosis is present.
  • Life-long abstinence is the best advice and is essential for those with more severe liver disease.
  • Treatment for complications of cirrhosis, such as variceal bleeding, encephalopathy and ascites, may also be needed. (Raff and Singal 2014)

NUTRITION

  • Good nutrition is very important and enteral feeding via a fine-bore nasogastric tube may be needed in severely ill patients. (Koretz 2014)

ASCITES

  • Patients with pure severe AH in the absence of cirrhosishave relatively little problem with ascites.
  • They eat so little that they do not take in enough sodium to retain much fluid.
  • Maintenance intravenous fluids should be avoided to minimize fluid retention.
  • When cirrhosis is also present, they may have more problematic fluid retention. In this case, if blood urea nitrogen and creatinine are normal, spironolactone can be given.
  • This drug will increase urinary excretion of sodium and water, increase serum potassium, and decrease the need for potassium supplementation.
  • Once serum potassium is normal without supplementation, oral furosemide can be added, if needed.
  • If azotemia occurs, diuretics should be stopped and the patient should be evaluated for hepatorenal syndrome. (Israelsen, Gluud et al. 2014)
  • The first step is to give 1 g of 25% albumin/kg body weight (100 g maximum) intravenously daily for 2 d and to monitor creatinine.
  • If creatinine improves with albumin, the azotemia is probably diuretic-induced. If creatinine continues to rise, hepatorenal syndrome is probably present, as this commonly occurs in severe AH.

VARICEAL HEMORRHAGE

  • patients with pure severe AH in the absence of cirrhosis have relatively little problem with upper gut hemorrhage.
  • The relatively short duration of AH usually does not lead to formation of varices that are large enough to bleed.
  • However, patients with underlying cirrhosis can bleed from esophageal varices.
  • Urgent endoscopy with banding of varices is warranted when this occurs.
  • Patients with severe AH are very intolerant of hypotension and seldom survive shock superimposed on AH.(Li, Liu et al. 2013)

CORTICOSTEROIDS IN ALCOHOLIC HEPATITIS

  • In severe alcoholic hepatitis corticosteroids improve survival at 28 days from 65% to 85% Sepsis is the main side-effect of steroids, and existing sepsis and variceal haemorrhage are the main contraindication to their use.
  • If the bilirubin has not fallen 7 days after starting steroids, they are unlikely to reduce mortality and should be stopped

PENTOXIFYLLINE IN ALCOHOLIC HEPATITIS

  • In severe alcoholic hepatitis, oral pentoxifylline reduces inpatient mortality, particularly from hepatorenal failure, from 46% to 25% (Joshi, Manori et al. 2013)
  • Pentoxifylline, which has a weak anti-TNF action. It appears to reduce the incidence of hepatorenal failure and its use is not complicated by sepsis
  • Baclofen has recently been evaluated in terms of safety and efficacy in the setting of alcoholic cirrhosis.
  • Baclofen significantly reduced alcohol cravings and significantly lengthened time to relapse with no significant adverse effects noted after 12 wk of continuous use in a well run randomized, controlled trial
  • Discharge is considered as the bilirubi level approaches 10 mg/dL, and the clinician can use this to help plan initiation of baclofen

PRONOSIS

MADDREY’S SCORE(Forrest 2014)

  • Maddrey’s score, which enables the clinician to assess prognosis in alcoholic hepatitis
  • PT = prothrombin time. Serum bilirubin in μmol/l is divided by 17 to convert to mg/dl):

The Maddrey discriminant function (DF) = [4.6 × (prothrombin time (PT)  – control PT) + serum bilirubin (mg/dL)]

  • A cutoff value of 32 is used to identify patients with a mortality rate above 50% without pharmacologic therapy.

MODEL FOR END-STAGE LIVER DISEASE

  • MELD uses the patient’s values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival. It is calculated according to the following formula

MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43×aetiology(0: cholestatic or alcoholic, 1- otherwise)

  • If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0
  • Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used)
  • In interpreting the MELD Score in hospitalized patients, the 3 month mortality is:
    • 40 or more — 71.3% mortality
    • 30–39 — 52.6% mortality
    • 20–29 — 19.6% mortality
    • 10–19 — 6.0% mortality
    • <9 — 1.9% mortality

CHILD-PUGH SCORE

  • used to assess the prognosis of chronic liver disease
Measure 1 point 2 points 3 points
Total bilirubin, μmol/l (mg/dl) <34 (<2) 34-50 (2-3) >50 (>3)
Serum albumin, g/dl >3.5 2.8-3.5 <2.8
PT INR <1.7 1.71-2.30 > 2.30
Ascites None Mild Moderate to Severe
Hepatic encephalopathy None Grade I-II (or suppressed with medication) Grade III-IV (or refractory)
Points Class One year survival Two year survival
5-6 A 100% 85%
7-9 B 81% 57%
10-15 C 45% 35%

References

Bruguera, M. (2014). “[Liver diseases in the elderly.].” Gastroenterol Hepatol.

Liver diseases in the elderly have aroused less interest than diseases of other organs, since the liver plays a limited role in aging. There are no specific liver diseases of old age, but age-related anatomical and functional modifications of the liver cause changes in the frequency and clinical behavior of some liver diseases compared with those in younger patients. This review discusses the most important features of liver function in the healthy elderly population, as well as the features of the most prevalent liver diseases in this age group, especially the diagnostic approach to the most common liver problems in the elderly: asymptomatic elevation of serum transaminases and jaundice.

Forrest, E. (2014). “Letter: Prognostic scores in alcoholic hepatitis.” Aliment Pharmacol Ther 39(11): 1340-1341.

Israelsen, M. E., et al. (2014). “Acute kidney injury and hepatorenal syndrome in cirrhosis.” J Gastroenterol Hepatol.

Cirrhosis is the eighth leading cause of “years of lost life” in the US and accounts for approximately 1 to 2% of all deaths in Europe. Patients with cirrhosis have a high risk of developing acute kidney injury. The clinical characteristics of HRS are similar to prerenal uraemia, but the condition does not respond to volume expansion. HRS type 1 is rapidly progressive whereas HRS type 2 has a slower course often associated with refractory ascites. A number of factors can precipitate HRS such as infections, alcoholic hepatitis and bleeding. The monitoring, prevention, early detection and treatment of HRS are essential. This paper reviews the value of early evaluation of renal function based on two new sets of diagnostic criteria. Interventions for HRS type 1 include terlipressin combined with albumin. In HRS type 2 transjugular intrahepatic portosystemic shunt (TIPS) should be considered. For both types of HRS patients should be evaluated for liver transplantation.

Joshi, P., et al. (2013). “Pentoxifylline in severe alcoholic hepatitis: a prospective, randomised trial.” J Assoc Physicians India 61(5): 354.

Koretz, R. L. (2014). “The evidence for the use of nutritional support in liver disease.” Curr Opin Gastroenterol 30(2): 208-214.

PURPOSE OF REVIEW: Although there is a well established association between malnutrition and poorer clinical outcomes in patients with liver disease, that fact alone does not prove that improving the malnutrition will improve outcome. The best way to determine if nutritional interventions are effective is to compare them to untreated control groups in well designed and executed randomized clinical trials. RECENT FINDINGS: A recent systematic review assessed 37 trials that compared parenteral nutrition, enteral nutrition, or nutritional supplements to no nutritional therapy in patients with a variety of liver diseases. Since the publication of that review, an additional three trials have become available. Whereas all but one of the trials did have methodologic shortcomings that may have allowed the introduction of bias (which usually results in an overestimation of benefit), the trials failed to show much, if any, benefit. In fact, the single trial at low risk of bias found that more deaths occurred in the recipients of the supplements. SUMMARY: Although malnutrition may be associated with a poor outcome, the current best evidence indicates that the provision of adjunctive nutritional support (parenteral or enteral nutrition, or nutritional supplements) to patients with a variety of liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, liver surgery, liver transplantation, obstructive jaundice, hepatitis C antiviral treatment) does not improve clinical outcomes.

Leake, I. (2014). “Alcoholic hepatitis: potential role of cytokine CCL20 in alcoholic hepatitis.” Nat Rev Gastroenterol Hepatol 11(2): 76.

Leslie, T., et al. (2014). “Survey of health status, nutrition and geography of food selection of chronic liver disease patients.” Ann Hepatol 13(5): 533-540.

Background. Obesity, a complex disease determined both by genetic and environmental factors, is strongly associated with NAFLD, and has been demonstrated to have a negative impact on HCV and other chronic liver diseases (CLD). Rationale. This study assessed the association between type and location of food sources and chronic liver disease (CLD) using Geographic Information Systems (GIS). Results. CLD patients completed surveys [267 subjects, 56.5% female, age 55.8 +/- 12.0, type of CLD: 36.5% hepatitis C (HCV), 19.9% hepatitis B (HBV), 19.9% non-alcoholic fatty liver disease (NAFLD); primary food source (PFS): 80.8% grocery store, secondary: 26.2% bulk food store, tertiary: 20.5% restaurants; fresh food (FF): 83%, pre-packaged (PP) 8.7%, already prepared (AP) 8.3%]. FF consumers had significantly fewer UEH servings/month (p = 0.030) and lived further away from convenience stores (1.69 vs. 0.95 km, p = 0.0001). Stepwise regression reveals the lowest FF consumers were NAFLD patients, subjects with UEH or restaurants and ethnic food stores as their PFS (R = 0.557, p = 0.0001). Eating already-packaged foods and utilizing restaurants or ethnic food stores as the PFS positively correlated with NAFLD (R = 0.546, p = 0.0001). Conclusions. Environmental food source measures, including type and density, should be included when examining areas hyper-saturated with a variety of food options. In hyper-saturated food environments, NAFLD patients consume more prepared food and less FF. CLD patients with UEH also eat significantly more prepared food and frequent restaurants and ethnic food stores as their PFS.

Li, N., et al. (2013). “[A retrospective analysis of ectopic varices in gastrointestinal tract diagnosed by endoscopy].” Zhonghua Nei Ke Za Zhi 52(11): 936-939.

OBJECTIVE: To understand the incidence, causes, clinical manifestations and treatment of ectopic varices (EV) in gastrointestinal (GI) tract. METHODS: GI endoscopic examinations were carried out in 99 783 patients from January 2004 to October 2012 in General Hospital of PLA. Sixty-four cases of ectopic varices in GI tract were discovered. The clinical manifestations of EV patients and treatment were analyzed retrospectively. The literatures of EV were reviewed. RESULTS: The prevalence of EV in GI was 0.06% (64/99 783) in all patients undergoing endoscopic examinations, including 5 in the gastric antrum, 37 in the duodenum, 2 in the colon, 17 in the rectum, 1 in terminal ileum as well as whole colorectum, and 2 in the anastomotic stomas. The causes of EV included portal hypertension with cirrhosis in 52 cases (42 of hepatitis as dominant, 5 of alcoholic, 3 of biliary). Twenty-five cases had past history of endoscopic sclerotherapy, tissue adhesive injection or band ligation.Extrahepatic portal vein obstruction was seen in 4 cases (1 with pancreatic cancer, gastric cardia after surgery, pancreatic cancer after surgery, small intestine after partial hepatectomy respectively) and 8 cases uncertain. Nine cases accepted endoscopic tissue adhesive injection (no post-operative hemorrhage occurred in 9 cases and EV disappeared in 3 cases). Endoscopic band ligation was performed only for one patient. CONCLUSIONS: EV in GI tract is a rare condition, which occurs commonly in duodenum, colon, and rectum. Portal hypertension is the most common cause. Gastrointestinal hemorrhage is the main clinical manifestation. EV should be considered in GI bleeding, with gastroesophageal varices hemorrhage excluded. Endoscopic adhesive injection is an effective way to treat EV.

Marra, F. and F. Tacke (2014). “Roles for Chemokines in Liver Disease.” Gastroenterology 147(3): 577-594 e571.

Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alcoholic steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic viral hepatitis, CCL5 and CXCL10 regulate the cytopathic versus antiviral immune responses of T cells and natural killer cells. During development of nonalcoholic steatohepatitis, CCL2 and its receptor are up-regulated in the liver, where they promote macrophage accumulation, inflammation, fibrosis, and steatosis, as well as in adipose tissue. CCL2 signaling thereby links hepatic and systemic inflammation related to metabolic disorders and insulin resistance. Several chemokine signaling pathways also promote hepatic fibrosis. Recent studies have shown that other chemokines and immune cells have anti-inflammatory and antifibrotic activities. Chemokines and their receptors can also contribute to the pathogenesis of hepatocellular carcinoma, promoting proliferation of cancer cells, the inflammatory microenvironment of the tumor, evasion of the immune response, and angiogenesis. We review the roles of different chemokines in the pathogenesis of liver diseases and their potential use as biomarkers or therapeutic targets.

Raff, E. and A. K. Singal (2014). “Optimal management of alcoholic hepatitis.” Minerva Gastroenterol Dietol 60(1): 25-38.

Alcoholic hepatitis, a clinical syndrome among people with chronic and active alcohol abuse presents with with jaundice and liver failure with or without hepatic encephalopathy. In patients with severe episode, this condition has a potential for 40-50% mortality within a month of presentation. Corticosteroids and pentoxifylline, only available current treatment options provide only about 50% survival benefit. Response to corticosteroids can only be assessed at 1 week of initiation of these drugs using Lille score or documentation of improvement in bilirubin levels. Requirement of minimum 6 months abstinence for liver transplantation cannot be met for alcoholic hepatitis patients who fail to respond to steroids. Emerging data on the benefit of liver transplantation for select patients with first episode of severe AH with non-response to steroids are encouraging. There remains an unmet need for studies assessing newer therapeutic targets and drugs and for optimizing the currently available treatment options. In this regard, decision to promote clinical and translational research by the National Institute of Alcohol Abuse and Alcoholism will be helpful in improving survival of patients with alcoholic hepatitis.

Stimac, D., et al. (2013). “[Hepatitis C: who should be treated?].” Acta Med Croatica 67(4): 325-328.

Therapy is strongly recommended in patients with acute infection, patients with elevated ALT levels, patients with normal ALT level and F > or = 2 METAVIR score, in genotype 1 nonresponders and relapsers to antiviral therapy with triple therapy (pegylated interferon, ribavirin, bocaprevir or telaprevir), in patients with compensated cirrhosis and patients on hemodialysis. It is possible to treat patients with HBV and HIV co-infection, patients with severe HCV extrahepatic manifestations and patients with transplanted liver. Drug users and alcoholics can be treated after 6-month abstinence, but also with supportive therapy. This therapy is not recommended in patients with fulminant hepatitis, patients with persistent normal ALT levels and without fibrosis, in kidney transplant recipients and in pregnant women.

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