Week 6, 11 and 12 PHAR3911

Kidneys, Liver, and Solid-Organ Transplant

Functions of the liver

• Metabolism (carbohydrates, lipids and protein)

• Detoxification (drugs and toxins)

• Storage (carbs, fats, protein, iron, vitamins)

• Waste products removal (bilirubin)

• Plasma protein synthesis (albumin, clotting factors)

• Bile production

• Filtration, phagocytosis and antigen presentation

• Acid/Base balance (bicarbonate and H+)

Liver roles in carbohydrate metabolism

Glycogenesis (in response to insulin)

Glycogenolysis (in response to glucagon)

Gluconeogenesis (in response to glucagon)

Glucagon stimulates which processes in the liver?

• Glycogenolysis

• Gluconeogenesis

Insulin stimulates which process in the liver?

Glycogenesis

Liver roles in lipid metabolism

– Lipoprotein synthesis

– Oxidation of fats

– Synthesis of cholesterol, phospholipids, steroid hormones

– Metabolism of steroids

Jaundice, dark urine, pale stool is a sign of what?

Liver and biliary dysfunction - the bile is not clearing from the gallbladder (so bilirubin is building up systemically)

Liver roles in protein metabolism

• deamination and transamination of amino acids

• removal of ammonia via urea formation

• synthesis of amino acids

Hepatic encephalopathy is a sign of liver dysfunction in which area of metabolism?

Impaired hepatic protein metabolism - impaired removal of ammonia toxin, leading to brain dysfunction

Hyperaldosteronism, hypercortisolism or gonadal dysfunction are signs of liver dysfunction in which area of metabolism?

Impaired lipid metabolism (of cholesterol, phospholipids and steroid hormones)

Malabsorption of fats and fat-soluble vitamins is a sign of liver dysfunction in which liver role?

Impaired biliary clearance; biliary disease/dysfunction

Which cells of the liver remove bacteria

Kupffer cells

Increased total bilirubin is a sign of which diseases?

Anaemia such as

• haemolytic anaemia

• haemolytic disease of the newborn

• sickle cell anaemia

• pernicious anaemia

Increased conjugated bilirubin is a sign of which diseases?

• bile duct obstruction

• cirrhosis

• hepatitis

Is ALT specific or non-specific for liver function?

ALT: specific to the liver and liver damage, as it is found in hepatic cytosol and is not associated with other tissue.

Is ALP specific or non-specific for liver function?

ALP: non-specific, because other tissues can release ALP too, such as:

• bone

• bile duct

• placenta

Is AST specific or non-specific for liver function?

AST: non-specific, because it is found in many parts of the body, especially:

• muscle

Is bilirubin specific or non-specific for liver function?

Bilirubin: specific (specifically indicates liver excretion); build up indicates liver dysfunction specifically of excretion, as it is usually cleared by the liver. Causes the jaundice and the pale stool colour (pale stool because low bilirubin in faeces and high bilirubin in bloodstream).

What are the two liver aminotransferases (AKA transaminases)?

ALT: Alanine aminotransferase

AST: Aspartate aminotransferase

Is GGT specific or non-specific for liver function?

GGT: specific, changes reflect obstruction of biliary tract and damage of biliary capillaries.

Bilirubin and albumin reflect which liver functions?

– Bilirubin – excretory function

– Albumin – synthetic function

Which biomarker is easily influenced by alcohol?

GGT

Diagnostic criteria for liver disease

• ALT more than three times the upper limit of normal

OR

• ALP of more than twice the upper limit of normal

OR

• Total bilirubin more than twice the upper limit of normal if associated with any elevation of ALT or ALP

Paracetamol, aspirin and cocaine are examples of drugs associated with which type of drug-induced liver injury?

Predictable (intrinsic) drug-induced liver injury

Herbal medicines, antibiotics, NSAIDs are examples of drugs associated with which type of drug-induced liver injury?

Idiosyncratic (spontaneous) drug-induced liver injury

What is the onset and mechanism of idiosyncratic/spontaneous drug-induced liver injury

Delayed onset, may become apparent after 1-3 months

Usually due to formation of a toxic metabolite and may be driven by immune (allergenic) or non-immune (metabolic) mechanisms

What can be taken to relieve pruritis (itching) associated with liver injury / cholestatic liver disease?

cholestyramine

How to manage drug-induced liver injury

• Withdraw drug

• Supportive diet: high protein, high carbohydrate + energy

• cholestyramine (4 g/day) for severe pruritus

• If paracetamol: NAC antidote

What is Hy’s Law

Drug-induced liver injury leading to jaundice has a case fatality rate of 10-50% (without a transplant).

Which viral hepatitis subtypes usually resolve on their own without sequelae?

Hepatitis A and Hepatitis E

Is Hepatitis B curable?

No

Is Hepatitis C curable?

Yes

Which viral hepatitis sub-types have a vaccine?

Hep A and Hep B

What biomarker changes may suggest viral hepatitis?

• increased AST and ALT

• mildly elevated ALP

• presence of acute phase antibodies e.g. anti-HAV/IgM

If INR is significantly elevated in viral hepatitis, what should be administered?

Vitamin K

Chronic hepatitis is defined as hepatitis lasting more than ______

6 months

How is chronic hepatitis diagnosis confirmed?

Via liver biopsy

What is available for proven Hep-A or Hep-B exposures?

Human immunoglobulin

Hepatitis A vaccines are recommended for which patient groups?

Vaccine recommended for:

– Travelers to high-risk areas

– IV drug use

– Men who have sex with men

– Recipients of blood products

– People with occupational exposure

– Patients with chronic liver disease

Hepatitis B vaccines are recommended for which patient groups?

Universal vaccination recommended of all children from birth + boosters.

Hepatitis B management

Which patient groups are at risk of Hep-C?

Peg-interferon is used for which type of viral hepatitis?

Hepatitis B

What kind of antivirals are used to treat Hepatitis C?

DAAs (Direct Acting Antivirals)

What is steatosis also known as?

Fatty liver disease

What is NAFLD and NASH?

NAFLD: Non-Alcoholic Fatty Liver Disease

NASH: Non-Alcoholic Steatohepatitis

Progression of Fatty Liver Disease

1. NAFLD (asymptomatic, fat)

2. NASH (inflammation + fibrosis/scarring)

3. Liver Cirrhosis (severe fibrosis, end-stage liver damage)

Ascites and hepatomegaly are signs of

End-stage liver damage

Causes of liver cirrhosis

• Cryptogenic (unknown cause)

• Alcoholic liver disease

• Hepatitis B or C

• Autoimmune hepatitis

• Hemochromatosis

• Wilson disease

• Alpha-1 antitrypsin deficiency

• Drug-induced liver disease

• Type IV glycogen storage disease

Examples of two drugs that can cause liver cirrhosis

Methotrexate

Amiodarone

Management of hepatic encephalopathy

• Protein (>30g/day)

• Prebiotics

• Probiotics

• Antibiotics (e.g. rifamixin) to eliminate gut bacteria that produce ammonia

Minimum amount of protein a day for people with liver disorders and complications

> 30 g per day

Most validated non-invasive test for assessing liver cirrhosis?

Vibration-controlled transient elastography (VCTE) with FibroScan

Liver cirrhosis management

– Prevention: alcohol avoidance

– Nutrition: protein supplement intake (branched chain amino acids), low salt diet

– Supplemental vitamins

– Liver transplant

Management of ascites (fluid build up in the abdomen in end-stage liver damage)

– adequate protein/energy intake

– Na restriction

– Fluid restriction

– Avoid Na retention drugs e.g. NSAIDs

– Spironolactone

– Frusemide

– Paracentesis: remove fluid to relieve abdominal pain and respiratory distress.

How to prevent bleeding oesophageal varices?

Propanolol to reduce heart rate, lowering portal hypertension

Contraindications to liver transplant

• Advanced hepatocellular carcinoma

• Uncontrolled extrahepatic infection

• Active alcohol/substance misuse disorder

• Coronary/cerebrovascular disease

• Inadequate social support

Ten year survival rate for adults and children following liver transplant

Ten-year patient survival

• 72.3% for adults

• 85.2% for children

How does acute infection, inflammation and cirrhosis alter CYP enzyme activity?

• Cirrhosis reduces enzyme capacity

• Cytokines downregulate enzyme activity

The liver has the largest store of which vitamin? How many months does this storage last?

Vitamin A (50-60% of the body’s total supply)

10 months

Which vitamins does the liver store?

• Vitamin A

• Vitamin D

• Vitamin B12

Risk factors of Drug-Induced Kidney Injury

– History of CKD

– Advanced age

– Critical illness

Medicines most implicated in Drug-Induced Kidney Injury

– aminoglycosides,

– NSAIDs, ACEIs, ARBs,

– calcineurin inhibitor immunosuppressants (tacrolimus, cyclosporine)

– intravenous contrast dye,

– amphotericin,

– piperacillin/tazobactam plus vancomycin

– diuretics

Which drugs can cause pseudo-nephrotoxicity (no actual kidney damage despite raised markers)?

• mesalazine

• trimethoprim

A patient with declining renal function, high calcium levels and acute systemic symptoms may be presenting with…

Calcium alkali syndrome

What do you do to treat calcium alkali syndrome?

• IV pamidronate

• stop calcium and vitamin D supplements

Which statin presents a greater risk to the kidneys than all others?

Rosuvastatin

What is pseudohaematuria and what drug can cause it?

The false appearance of “blood” in urine.

Mesalazine reacting with toilet bleach can cause this effect.

When should dialysis be initiated?

AEIOU indications:

• Acidosis

• Electrolyte abnormality

• Intoxicants

• Overload (volume overload refractory to diuretics)

• Uremia

GFR indications:

• Stage G4: GFR less than 30

• Stage G5 (kidney failure): GFR less than 15

The two processes that drive dialysis

• Diffusion

• Convection

What is the preferred vascular access for hemodialysis and why?

A surgically-created AV fistula because it enables high pressure, fast blood flow

Haemodialysis duration and frequency

4-6 hours three times a week

Longer dialysis sessions means…

Longer dialysis means

• less diet and fluid restrictions

• improved health and quality of life

Two types of peritoneal dialysis and their differences

• continuous ambulatory peritoneal dialysis (CAPD): manual, moves with you

• automated peritoneal dialysis (APD): overnight via a cycler

CKD is defined as…

Kidney damage OR GFR below 60 ml/min/1.73sqm for 3 months or more

CKD risk factors

Main symptoms of uremia

• Cramps

• Restless legs

• Hiccups

• Coma

Top 2 causes of CKD

• Diabetes Mellitus (Type 2)

• Hypertension

CKD non-pharmacological management

• Smoking cessation

• Alcohol restriction

• Diet, including:

  • Sodium restriction

  • Phosphate restriction

  • Carbonated beverage restriction

  • If hyperkalaemic, potassium restriction

• Exercise

• Weight management

Preferred agents for managing hypertension in CKD

ACE inhibitors or ARBs

Dihydropyridine Calcium Channel Blockers are also beneficial

ACE inhibitors and ARBs are nephroprotective long term even though they can be nephrotoxic. An ACE inhibitor or ARB can be continued as long as…

As long as:

• eGFR does not deteriorate by more than 25% within 2 months of initiation

AND

• Potassium stays below 6 mmol/L

How to manage proteinuria or albuminuria?

• ACEI/ARBs

• reduce salt intake

• SGLT2 inhibitor

If a patient has CKD, they may need lipid management. What is the decision tree for this?

• Over the age of 50 years

  • eGFR greater than 60 mL/min: start statin only

  • eGFR below 60 mL/min: start statin and ezetimibe

• Under the age of 50 years

  • Coronary disease, previous stroke, diabetes or 10% risk of heart attack in 10 years time: start statin

Glucose control in CKD patients can be managed with which kinds of drugs?

• Oral hypoglycaemic agents

• Gliptins

• Incretin mimetic

• Insulin

• SGLT2 inhibitors

What different consequences of CKD need to be managed in a CKD patient?

• impaired glucose control

• hypertension

• dyslipidemia

• sodium imbalance

• impaired vitamin D and phosphorus metabolism

• anaemia

What therapies are used to maintain sodium balance in patients with CKD?

• Sodium restriction

• Diuretics (NOT potassium sparing)

Thiazide and related diuretics can be used in which stages of CKD?

Stages 1-3

(ineffective once GFR is below 30)

Loop diuretics can be used in which stages of CKD?

All stages

K+ -sparing diuretics can be used in which stages of CKD?

K+ -sparing diuretics are not usually used in CKD because they present an increased risk of hyperkalemia.

Main symptom of metabolic acidosis

Shortness of breath on exertion not explained by anything else

How is metabolic acidosis from CKD managed?

Not treated unless bicarb less than 15 mmol/l or pH less than 7.30

Can be treated with sodium bicarbonate (risk of high sodium)

Threshold for hyperkalemia

Potassium greater than 7 mmol/L

Acute hyperkalemia management

Calcium gluconate IV

Insulin and glucose IV

Sodium (or calcium) resonium orally or enema

Chronic hyperkalemia management

• stop drugs causing hyperkalaemia

• reduce dietary potassium

• correct acidosis:

  • Thiazides or loop diuretics to eliminate potassium

  • cation exchange resins (polystyrene sulfonate, Resonium )

Persistent pruritis in CKD patients can be managed with

UVB light phototherapy

Presentation of both restless legs AND pruritis symptoms in CKD can be managed with

gabapentin

Managing phosphorus and vitamin D metabolism in CKD: agents (classes) used

• Vitamin D supplements

• Phosphate binding agents

• Calcimimetics (Calcinet)

Which vitamin D supplements can be used in CKD?

Calcitriol

Paricalcitol

Cholecalciferol (if renal function is intact, or in combination with calcitriol in advanced CKD)

Which vitamin D supplement is only useful in renal function is intact?

Cholecalciferol

How is anaemia managed in CKD?

• ESA: erythropoiesis-stimulating agents

  • potentially iron, folate or B12 supplements alongside

• iron infusions

Hemoglobin (Hb) should not exceed ______ g/L (increased risk of CV events).

130 g/L