Alcohol-related jaundice Flashcards
What diseases are encompassed by the term alcoholic liver disease?
- alcoholic fatty liver (steatosis)
- alcoholic hepatitis
- cirrhosis
- (risk of hepatocellular carcinoma)
What is considered ‘heavy’ alcohol consumption?
>6 drinks per day on average
What proportion of individuals who consume alcohol heavily will develop alcoholic fatty liver disease?
90%
What proportion of deaths from cirrhosis is alcoholic liver disease thought to account for?
40% (28% of all deaths from liver disease)
What are the 2 broad categories into which the mechanisms underlying alcoholic liver injury can be placed?
- effects of alcohol directly on hepatocytes
- effects mediated by Kupffer cells
What are 5 hepatocyte-specific mechanisms through which alcoholic liver injury is thought to occur?
- the altered redox state induced by alcohol and aldehyde dehydrogenase reactions
- the oxidative stress and lipid peroxidation caused by the induction of CYP2E1 enzymes and the mitochondrial electron transfer system
- the effects of alcohol upon the nuclear transcription factors AMP kinase and SREBP-1c
- protein adduct formation
- altered methionine and folate metabolism with resulting stress on the endoplasmic reticulum
What are 4 stages of Kupffer cell-specific mechanisms through which alcoholic liver injury is thought to occur?
- Chronic alcohol consumption increases gut permeability, and the resulting portal endotoxemia activates Kupffer cells
- Activated Kupffer cells release a number of proinflammatory mediators, incl.:
- tumor necrosis factor-α (TNF-α)
- transforming growth factor-β1
- interleukins 1, 6, 8, and 10
- platelet-derived growth factor
- TNF-α has a plethora of biologic effects and causes hepatocyte apoptosis
- Transforming growth factor-β1 and platelet-derived growth factor play important roles in stellate cell activation, collagen production, and hepatic fibrosis
What are 4 different types of proinflammatory mediators released by Kupffer cells when they’re activated by chronic alcohol consumption?
- tumor necrosis factor-α (TNF-α)
- transforming growth factor-β1
- interleukins 1, 6, 8, and 10
- platelet-derived growth factor.
What is the effect of TNF-alpha when released by Kupffer cells?
hepatocyte apoptosis (and plethora of other biologic effects)
What is the effect of transforming growth factor-beta 1 and platelet-derived growth factor, when released by activated Kupffer cells?
important roles in stellate cell activation, collagen production, and hepatic fibrosis
What are 7 risk factors for alcoholic liver disease?
- Amount of alcohol consumed
- Women at higher risk than men
- Genetic factors
- Spirits and beer higher risk than wine
- Ethnicity e.g. Hispanic / native American
- Obesity
- Protein-calorie malnutrition
What are 4 examples of genetic changes that can predispose to alcoholic liver disease?
- Lipid metabolism: PNPLA3
- Alcohol metabolism: alcohol and aldehyde dehydrogenases
- Cytochrome P-450 enzymes
- Dysregulated cytokine production e.g. TNF-alpha
What are 3 examples of candidate genes for alcohol-related cirrhosis?
PNPLA3, TM6SF2, MBOAT7
What are 6 general clinical manifestations on examination of chronic alcoholism?
- Palmar erythema
- Spider naevi
- Bilateral gynaecomastia
- Testicular atrophy
- Bilateral parotid enlargement
- Dupuytren contracures
What are 6 possible clinical features of alcoholic fatty liver disease?
- Generally asymptomatic
- Anorexia
- Fatigue
- Right upper quadrant discomfort
- Tender hepatomegaly
- Typically do not have jaundice, ascites, or splenomegaly
What are 3 biochemical signs of alcoholic fatty liver disease?
- Macrocytosis
- Elevated AST
- Elevated gamma-GT
How does the presentation of alcoholic hepatitis compare with fatty liver disease?
typically alcoholic hepatitis more dramatic
What are 6 classic features of acute alcoholic hepatitis?
- Severe malaise
- Fatigue
- Anorexia
- Fever
- Protein-calorie malnutrition
- Features of decompensated liver disease
- jaundice
- coagulopathy
- ascites
- encephalopathy
What are 6 typical findings on blood tests in alcoholic hepatitis?
- Leucocytosis with neutrophil predominance
- Macrocytic anaemia
- Thrombocytopenia
- Prolonged prothrombin time
- Raised AST and raised ratio of AST to ALT, ALP, gGT, total bilirubin
- Decreased levels of serum albumin
- Hypokalaemia, hypomagnesaemia, hypocalcaemia, hypophosphataemia
What is the presentation of alcoholic liver cirrhosis like?
clinical features common to other types of cirrhosis:
- fatigue and anergia
- anorexia and cachexia
- nausea or abdominal pain
- spider naevi
- gynaecomastia
but also with striking features of underlying chornic alcoholism incl. significant muscle wasting
How is a diagnosis of alcoholic liver disease made?
- history of excessive alcohol consumption and presence of liver disease
- AST/ALT ratio >2 typical of alcoholic liver disease
- Hepatic imaging:
- ultrasound
- CT
- MRI
- Liver biopsy
What is the typical AST/ALT finding in alcoholic liver disease?
AST:ALT ratio >2
What are 3 types of imaging that can be used to diagnose alcoholic liver disease?
ultrasound, CT, MRI
can show steatosis, cirrhosis/portal hypertension
What are 2 other types of liver disease that imaging can exclude in alcoholic liver disease?
malignancy disease
biliary obstruction
What are 4 imaging findings specific for alcoholic liver disease?
- Enlarged caudate lobe
- Greater visualisation of the righ tposterior hepatic notch
- Focal fat sparing
- Geographic fat distribution
What are 2 specific forms of other predominant or coexisting liver diseases that it is important to exclude and why?
- Chronic viral hepatitis
- Drug-induced liver injury (esp paracetamol)
specific treatment for alcoholic hepatitis may be harmful in these patients
What is the key investigation for distinguishing alcoholic liver disease from other entities? What else can it show?
liver biopsy
can determine whether fatty liver or more advanced alcoholic hepatitis
What will biopsy show in alcoholic fatty liver?
macrovesicular steatosis, predominantly centrilobular
What will biopsy show in alcoholic hepatitis? 6 features
- macrovesicular steatosis
- lobular neutrophilic infiltration
- Mallory hyaline
- balloon degeneration of hepatocytes
- perivenular firbosis
- more advanced fibrosis: periportal or bridging fibrosis or cirrhosis
What is the most important treatment measure for alcoholic liver disease?
total alcohol abstinence - multidisciplinary approach
What are 3 types of drugs which can be used to help promote alcohol abstinence?
- Disulfiram
- Acamprosate
- Opioid antagonists e.g. naltrexone, nalmefene
Why does disulfiram promote abstinence?
alcohol intake causes severe reaction due to inhibition of acetaldehyde dehydrogenase
even small amounts of alcohol (perfumes, foods, mouthwash) can produce severe symptoms
What are 2 contraindications to disulifram?
- Ischaemic heart disease
- Psychosis
What is the mechanism of action of acamprosate to promote abstinence?
reduces craving, known to be a weak antagonist of NMDA receptors
What is the approach to managing alcoholic fatty liver disease?
no specific treatment other than abstinence
What is the management of alcoholic hepatitis? 3 main aspects
consider therapeutic interventions in addition to mandatory abstinence
- Predisnolone used for acute episodes of hepatitis
- Pentoxyphylline sometimes used (inferior to prednisolone)
- can add NAC to prednisolone (shown to be beneficial in trials)
What are 2 aspects of management of alcoholic cirrhosis?
- assess and treat for protein-calorie malnutrition and micronutrient deficiency (thiamine)
- hospitalised patients with severe decompesnation should be considered for enteral nutrition
What is the function used to determine who would benefit from glucocorticoid therapy during acute episodes of hepatitis?
Maddrey’s discriminant function (DF): formula uses prothrombin time and bilirubin concentration
What are 2 contraindications to using prednisolone in acute hepatitis?
- gastrointestinal bleeding
- systemic infection
What are 2 types of severity scoring systems for liver cirrhosis?
- Child-Pugh classification (older)
- Model for End-Stage Liver Disease (MELD)
What are 7 complications which may occur in patients with decompensated alcoholic cirrhosis?
- Ascites
- Spontaneous bacterial peritonitis
- Encephalopathy
- Variceal bleeding
- Hepatorenal syndrome
- Osteoporosis
- Hepatopulmonary syndrome
What is a key treatment option to consider in patients with decompensated alcoholic cirrhosis?
liver transplantation
When is the MELD scoring system often used?
patients on liver transplant waiting list
In the UK how long is abstinence needed to be referred for liver transplant?
3 months (with evidence from random blood alcohol levels, alcohol metabolite testing, support from addition services)
What disease are patients with alcoholic cirrhosis at risk of an what screening is performed for this?
- hepatocellular carcinoma
- annual liver imaging and serum alpha-fetoprotein levels
What is a specific treatment for Dupuytren’s contracture?
injection of collagenase clostridium histolyticum - can reduce severity and improve range of motion
What proportion of patients with alcoholic hepatitis die within 6 months after presentation?
20%
What are 4 predictors of poor outcomes in alcoholic cirrhosis?
- MELD score
- Severity of fibrosis
- Neutrophilic infiltration on liver biopsy
- Continued alcohol use
