Disorders of carbohydrate metabolism: Pathology review

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Disorders of carbohydrate metabolism: Pathology review

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Tuberculosis: Pathology review
Obstructive lung diseases: Pathology review
Restrictive lung diseases: Pathology review
Apnea, hypoventilation and pulmonary hypertension: Pathology review
Lung cancer and mesothelioma: Pathology review
Deep vein thrombosis and pulmonary embolism: Pathology review
Pneumonia: Pathology review
Respiratory distress syndrome: Pathology review
Cystic fibrosis: Pathology review
Disorders of sex chromosomes: Pathology review
Prostate disorders and cancer: Pathology review
Testicular tumors: Pathology review
Uterine disorders: Pathology review
Ovarian cysts and tumors: Pathology review
Cervical cancer: Pathology review
Benign breast conditions: Pathology review
Complications during pregnancy: Pathology review
Congenital TORCH infections: Pathology review
Breast cancer: Pathology review
Vaginal and vulvar disorders: Pathology review
Androgens and antiandrogens
Adrenergic antagonists: Alpha blockers
PDE5 inhibitors
Estrogens and antiestrogens
Uterine stimulants and relaxants
Aromatase inhibitors
Progestins and antiprogestins
Congenital renal disorders: Pathology review
Renal tubular defects: Pathology review
Renal tubular acidosis: Pathology review
Acid-base disturbances: Pathology review
Electrolyte disturbances: Pathology review
Kidney stones: Pathology review
Renal and urinary tract masses: Pathology review
Osmotic diuretics
Loop diuretics
Potassium sparing diuretics
Carbonic anhydrase inhibitors
Thiazide and thiazide-like diuretics
ACE inhibitors, ARBs and direct renin inhibitors
Congenital neurological disorders: Pathology review
Headaches: Pathology review
Seizures: Pathology review
Cerebral vascular disease: Pathology review
Traumatic brain injury: Pathology review
Spinal cord disorders: Pathology review
Dementia: Pathology review
Central nervous system infections: Pathology review
Movement disorders: Pathology review
Demyelinating disorders: Pathology review
Adult brain tumors: Pathology review
Pediatric brain tumors: Pathology review
Neurocutaneous disorders: Pathology review
General anesthetics
Local anesthetics
Neuromuscular blockers
Back pain: Pathology review
Rheumatoid arthritis and osteoarthritis: Pathology review
Gout and pseudogout: Pathology review
Seronegative and septic arthritis: Pathology review
Systemic lupus erythematosus (SLE): Pathology review
Bone disorders: Pathology review
Bone tumors: Pathology review
Myalgias and myositis: Pathology review
Neuromuscular junction disorders: Pathology review
Pigmentation skin disorders: Pathology review
Acneiform skin disorders: Pathology review
Vesiculobullous and desquamating skin disorders: Pathology review
Papulosquamous and inflammatory skin disorders: Pathology review
Skin cancer: Pathology review
Immunodeficiencies: T-cell and B-cell disorders: Pathology review
Immunodeficiencies: Phagocyte and complement dysfunction: Pathology review
Immunodeficiencies: Combined T-cell and B-cell disorders: Pathology review
Microcytic anemia: Pathology review
Non-hemolytic normocytic anemia: Pathology review
Intrinsic hemolytic normocytic anemia: Pathology review
Extrinsic hemolytic normocytic anemia: Pathology review
Macrocytic anemia: Pathology review
Heme synthesis disorders: Pathology review
Mixed platelet and coagulation disorders: Pathology review
Leukemias: Pathology review
Myeloproliferative disorders: Pathology review
Anticoagulants: Heparin
Anticoagulants: Warfarin
Anticoagulants: Direct factor inhibitors
Antiplatelet medications
Congenital gastrointestinal disorders: Pathology review
Esophageal disorders: Pathology review
Inflammatory bowel disease: Pathology review
GERD, peptic ulcers, gastritis, and stomach cancer: Pathology review
Malabsorption syndromes: Pathology review
Diverticular disease: Pathology review
Gastrointestinal bleeding: Pathology review
Appendicitis: Pathology review
Colorectal polyps and cancer: Pathology review
Pancreatitis: Pathology review
Jaundice: Pathology review
Viral hepatitis: Pathology review
Cirrhosis: Pathology review
Eye conditions: Refractive errors, lens disorders and glaucoma: Pathology review
Eye conditions: Retinal disorders: Pathology review
Vertigo: Pathology review
Eye conditions: Inflammation, infections and trauma: Pathology review
Nasal, oral and pharyngeal diseases: Pathology review
Adrenal insufficiency: Pathology review
Adrenal masses: Pathology review
Hypothyroidism: Pathology review
Hyperthyroidism: Pathology review
Thyroid nodules and thyroid cancer: Pathology review
Parathyroid disorders and calcium imbalance: Pathology review
Cushing syndrome and Cushing disease: Pathology review
Diabetes mellitus: Pathology review
Pituitary tumors: Pathology review
Hypopituitarism: Pathology review
Multiple endocrine neoplasia: Pathology review
Diabetes insipidus and SIADH: Pathology review
Acyanotic congenital heart defects: Pathology review
Cyanotic congenital heart defects: Pathology review
Atherosclerosis and arteriosclerosis: Pathology review
Coronary artery disease: Pathology review
Peripheral artery disease: Pathology review
Valvular heart disease: Pathology review
Cardiomyopathies: Pathology review
Heart failure: Pathology review
Supraventricular arrhythmias: Pathology review
Aortic dissections and aneurysms: Pathology review
Pericardial disease: Pathology review
Endocarditis: Pathology review
Shock: Pathology review
Hypertension: Pathology review
Vasculitis: Pathology review
Cardiac and vascular tumors: Pathology review
Autosomal trisomies: Pathology review
Miscellaneous genetic disorders: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review
Purine and pyrimidine synthesis and metabolism disorders: Pathology review
Disorders of carbohydrate metabolism: Pathology review
Disorders of fatty acid metabolism: Pathology review
Glycogen storage disorders: Pathology review
Dyslipidemias: Pathology review
Lysosomal storage disorders: Pathology review
Fat-soluble vitamin deficiency and toxicity: Pathology review

Assessments

USMLE® Step 1 questions

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Questions

USMLE® Step 1 style questions USMLE

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A 27-year-old woman comes to her primary care physician for evaluation of bloating and flatulence. The patient’s symptoms have been ongoing for several months and tend to occur after she consumes ice cream or milk. The patient has not lost weight or noticed blood in her stool since symptom onset. Family history is notable for Crohn disease in the patient’s mother. Temperature is 37.0°C (98.6°F), blood pressure is 112/72 mmHg, pulse is 71/min, and respiratory rate is 14/min. Physical examination is unremarkable. Fecal occult blood test is negative. The patient is scheduled for a hydrogen breath test, which returns positive. Which of the following best describes the underlying cause of this patient’s symptoms?  

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A 5 day old newborn infant girl named Emily is brought to the emergency department due to vomiting, diarrhea, and poor feeding. Her mother also mentions that Emily seems to be tired and sleepy all day long. Physical examination reveals bilateral clouding of the lens, along with yellowing of the sclera. Upon palpation of the abdomen, Emily’s liver appears enlarged. Emily’s mother mentions that she lives in a remote area and gave birth at home. You decide to run a urine dipstick test, which comes back negative for sugars, followed by a nonspecific urine test, which shows increased levels of reducing sugars. Some days later, you see a 21 year old man of Asian descent named Chris, who’s complaining of repeated episodes of bloating, abdominal cramps, and excessive flatulence that are often associated with watery, frothy stool. He has noticed that his symptoms tend to occur when he eats cheese or ice cream. Upon further questioning, he denies any concomitant diseases or recent gastrointestinal infections. Physical examination is unremarkable. Okay, based on the history and initial presentation, both Emily and Chris seem to have some form of disorder of carbohydrate metabolism. Carbohydrates are our main source of energy, and can be classified as simple or complex. Simple carbohydrates include monosaccharides, which contain one sugar molecule, like glucose, fructose, and galactose; and disaccharides, where two sugar molecules are linked together. Disaccharides include lactose, which is made up of glucose and galactose, and sucrose, which is formed when glucose links up with fructose. On the other hand, complex carbohydrates include oligosaccharides and polysaccharides, which are respectively short and long chains made up of more than two sugar molecules. All right, now, for your exams, the most high yield disorders of carbohydrate metabolism include pyruvate dehydrogenase complex deficiency, galactosemia, disorders of fructose metabolism, and lactose intolerance. Let’s begin with pyruvate dehydrogenase complex deficiency or PDC deficiency. This is mainly caused by mutations in the PDHA1 gene, which is located on the X chromosome. So, PDC deficiency is an X-linked recessive disorder, which means that all carrier males develop the disease, because they only have one X chromosome and thus one PDHA1 gene available. On the other hand, females have two X chromosomes, so having a single mutation makes them a carrier, and two mutations are needed to have the disease. Now, the PDHA1 gene codes for one of the enzymes of the pyruvate dehydrogenase complex or PDC for short. Normally, after a meal, glucose is broken down into pyruvate in the cytoplasm through a process called glycolysis. Pyruvate can then enter the mitochondria, where a complex of three mitochondrial enzymes, called the pyruvate dehydrogenase complex, converts pyruvate into acetyl-CoA. Acetyl-CoA can then be used in the Krebs cycle, also known as the tricarboxylic acid or TCA cycle, to produce energy in the form of ATP. For your exams, remember that the pyruvate dehydrogenase complex requires a set of 5 cofactors to work properly. To help you remember these 5 cofactors, think of the mnemonic “The Lovely Coenzymes For Nerds”, which stands for thiamine pyrophosphate, which is a derivative of thiamine or vitamin B1; lipoic acid; CoA; which is a derivative of pantothenic acid or vitamin B5; FAD, which is a riboflavin or vitamin B2 derivative; and NAD+, which is a niacin or vitamin B3 derivative.

Okay, so, with PDC deficiency, acetyl-CoA levels fall, causing the Krebs cycle to slow down, and as a result, there’s decreased production of ATP. For your exams, keep in mind that this primarily affects cells with high energy requirements like neurons. At the same time, pyruvate builds up, so it gets converted to lactate by the enzyme lactate dehydrogenase or LDH for short, as well as to alanine by alanine aminotransferase or ALT. Symptoms of PDC deficiency typically begin during infancy and include lethargy or extreme lack of energy, hypotonia or weak muscle tone, and poor feeding. In addition, PDC deficiency may lead to developmental delay, intellectual disability, and seizures. For diagnosis, lab tests show elevated blood levels of alanine and, most importantly, lactate, which is known as lactic acidosis and it’s extremely high yield for your exams! Treatment of PDC deficiency consists of correcting the acidosis, as well as adopting a ketogenic diet, which is a diet low in carbohydrates and high in fat and ketogenic amino acids like lysine or leucine. This diet results in the generation of ketone bodies, which can be used as an alternative energy source by tissues around the body and especially, by the brain. Okay, next is galactosemia, which refers to defects in the metabolism of galactose. The normal pathway of galactose metabolism starts with the enzyme galactokinase, which converts galactose to galactose 1-phosphate, that can’t exit the cells. Galactose 1-phosphate is then converted by the enzyme uridyltransferase to glucose 1-phosphate, which can then enter the gluconeogenesis pathway to make more glucose or the glycolysis pathway to produce energy. Now, some of the galactose undergoes an alternate pathway, where it’s broken down by the enzyme aldose reductase into galactitol, which is then excreted in the urine. For your exam, remember that there are two types of galactosemia. The most common one is type I or classic galactosemia, which is caused by a deficiency in galactose-1-phosphate uridyltransferase or GALT for short; while type II galactosemia is caused by a deficiency of galactokinase. Keep in mind is that both types are autosomal recessive, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition. Now, both type I and type II galactosemia typically present early on, as soon as the infant begins breastfeeding, since breast milk contains lactose that’s digested by the enzyme lactase into galactose and glucose. So, with galactosemia, all this galactose ends up being converted to galactitol by aldose reductase. The excess galactitol mainly accumulates in the lens of the eye and attracts water, which ultimately causes the lens fiber to swell until they rupture. This is called osmotic cellular injury, and it quickly leads to infantile cataracts, which refers to clouding or opacification of the lens. Now, the main symptom of cataracts is a painless visual impairment that’s often bilateral, and these infants may present as a failure to track objects or to develop a social smile in response to someone else’s smile because they can’t see that well. For your exams, another telltale sign is leukocoria or “white pupil”, which is an abnormal white reflection from the retina of the eye, also called a white pupillary reflex.

What you definitely need to know for your exams is that type I galactosemia is much more severe. That’s because galactose can still be converted into galactose 1-phosphate. So, in addition to galactitol build up leading to cataracts, type I galactosemia also has a buildup of galactose-1-phosphate, which gets trapped inside the cells of the liver and brain. So, symptoms include hepatomegaly or liver enlargement associated with jaundice. In addition, there’s lethargy and intellectual disability, as well as nausea, vomiting, diarrhea, and poor feeding; which combined result in failure to thrive. And a life-threatening complication you should definitely know is sepsis, particularly by E. coli infection. Diagnosis of galactosemia is based on blood tests that show elevated galactose in blood. Some of the excess galactose is excreted in the urine, resulting in galactosuria. Don’t let examiners confuse you by mentioning that a urine dipstick was negative for sugars! Remember that this refers to glucose only, but there are nonspecific urine tests that can detect reducing sugars, such as galactose, fructose, and lactose. So, if there's some reducing sugar other than glucose in the urine, we're gonna get a negative urine dipstick test and a positive reducing test. In many countries, these tests are performed as a uniform newborn screening. Diagnosis can be confirmed with a blood test by measuring reduced enzymatic activity of GALT or galactokinase, respectively for type I and II, and they’re both treated with a diet free of galactose and lactose for life. Moving on to disorders of fructose metabolism, these include essential fructosuria and hereditary fructose intolerance, both of which are autosomal recessive. Normally, fructose is first converted to fructose-1-phosphate by fructokinase, which can’t exit the cells. And that fructose-1-phosphate is broken down by aldolase B to be used for gluconeogenesis or glycolysis. Now, some of the fructose can undergo an alternate pathway, where it’s converted by the enzyme hexokinase to fructose-6-phosphate, which can also be used for gluconeogenesis or glycolysis. Now, in essential fructosuria, there’s a deficiency of fructokinase. This means that fructose can’t be converted to fructose-1-phosphate, so it builds up. The good news is that fructose itself is not toxic, and it’s just gonna get excreted in the urine. In addition, remember that some of that excess fructose can still be converted to fructose-6-phosphate by hexokinase. So essential fructosuria is asymptomatic. Diagnosis typically relies on a positive reducing test of the urine, whereas confirmation is done with a blood test showing reduced enzymatic activity of fructokinase. Fortunately, no treatment or specific diet is necessary for essential fructosuria. In contrast, hereditary fructose intolerance is caused by a deficiency of aldolase B. This results in the buildup of fructose-1-phosphate, which is actually toxic, so it can cause pretty serious problems as soon as the infant starts consuming fructose from fruit, honey, or juice. Initially, symptoms include lethargy, nausea, and vomiting. In addition, hereditary fructose intolerance may cause renal damage, which can ultimately lead to kidney failure. But what's even more high yield is that there’s liver damage, leading to hepatomegaly and jaundice, as well as severe hypoglycemia or low levels of blood glucose. That’s because fructose-1-phosphate can’t enter gluconeogenesis in the liver. In addition, fructose-1-phosphate acts as a phosphate sink that takes up all the phosphate, reducing the amount of ATP available to synthesize glucose. Diagnosis once again involves a positive reducing test and can be confirmed by finding low levels of aldolase B in a liver biopsy. Treatment should begin as early as possible and requires lifelong exclusion of fructose and sucrose from the diet.

Sources

  1. "Robbins Basic Pathology" Elsevier (2017)
  2. "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
  3. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  4. "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
  5. "Carbohydrate metabolism" Surgery (Oxford) (2009)
  6. "A quick look at biochemistry: Carbohydrate metabolism" Clinical Biochemistry (2013)