Paroxysmal Nocturnal Hemoglobinuria (PNH)

Vignette says a 38 year old male presents to the primary care physician with chief complaints of passing dark colored urine in the morning over the past few months; He also reports of fatigue, generalized weakness, occasional headaches, shortness of breath, and intermittent abdominal pain over the past few months; He also reports of multiple episodes of unexplained anemia in the past, requiring occasional blood transfusions; He was previously diagnosed with deep venous thrombosis of the left lower extremity 1 year back and takes warfarin 5 mg once daily; Vital signs show blood pressure of 130/80 mm of Hg, pulse rate of 88 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 98% in RA and temperature of 96.9 F; Examination shows pale bulbar conjunctiva and palms; Laboratory studies show hemoglobin of 8.0 mg/dL, MCV of 100 fL, reticulocyte count of 4% (normal range is 0.5- 2.5%), LDH of 1200 U/L (normal range is 135-225 U/L), indirect bilirubin of 1.8 mg/dL (normal range is 0.2 to 0.8 mg/dL) and low haptoglobin levels; Coombs test is negative; Flow cytometry detects absence of anchored proteins CD55 and CD59; Diagnosis?

Diagnosis is Paroxysmal Nocturnal Hemoglobinuria (PNH).

Paroxysmal Nocturnal Hemoglobinuria (PNH) is caused by the mutation of PIGA gene in hematopoietic stem cells; PIGA gene is required for the synthesis of glycosylphosphatidylinositol (GPI) protein on cell surface; Mutation of PIGA gene leads to deficiency of GPI and subsequently deficiency of its anchored proteins CD55 and CD59 (CD55 and CD59 is secured to the cell membrane by GPI; CD55/DAF and CD59/MIRL are the inhibitors of complement).

Presents with coombs negative hemolytic anemia, pancytopenia and venous thrombosis.

Diagnosis:-

1. CBC shows pancytopenia.

2. Sucrose lysis test is used for screening.

3. Flow cytometry detects absence of anchored proteins CD55 and CD59 and is the confirmatory test. 

4. Laboratory studies show low hemoglobin, increased reticulocytes, increased indirect bilirubin, increased LDH and decreased haptoglobin.

Management:-

1. Supportive measures include iron, folate supplementation, blood transfusions and anticoagulation.

2. Steroids. 

3. Eculizumab is the monoclonal antibodies to C5 that inhibits activation of the terminal complement pathway) and reduces hemolysis; It is associated with increased susceptibility to neisseria infections. Hence, patients should receive meningococcal vaccination before receiving eculizumab.

4. Allogeneic bone marrow transplant.

Sjogren’s syndrome

Vignette says a 38 years old female presents to her primary care physician with chief complaints of dry eyes and dry mouths for the past 6 months; She reports of burning, itching and gritty sensation in both eyes and uses artificial tear drops frequently; She also reports of difficulty swallowing dry foods and needs to drink water frequently while eating foods; Examination shows non tender, enlarged bilateral parotid glands; She was diagnosed with rheumatoid arthritis 2 years back and takes 15 mg of methotrexate once weekly with folinic acid; Vital signs show blood pressure of 120/80 mm of Hg, pulse rate of 78 bpm, respiratory rate of 16 breaths/min, oxygen saturation of 98% in RA and temperature of 96.9 F; Serology shows positive ANA, rheumatoid factor, Anti SS-A (Ro) and Anti SS-B (La) antibodies; Schirmer test shows reduced tear production; Salivary gland biopsy shows lymphocytic infiltration; Diagnosis?

Diagnosis is Sjogren’s syndrome.

Sjogren’s syndrome is an autoimmune disease that leads to destruction of lacrimal and salivary glands due to lymphocytic infiltration; It commonly affects women; It can be divided into primary and secondary (associated with other autoimmune disorders like RA, SLE).

Clinical features:-
1. Dry eyes (keratoconjunctivitis sicca)
2. Dry mouth (xerostomia), dental caries
3. Symmetric painless enlargement of parotid glands
4. Vaginal dryness and dyspareunia
5. Dry skin
6. Extra glandular features include arthritis, vasculitis, interstitial nephritis, interstitial pneumonitis, PNS or CNS disease, PBC, Raynaud phenomenon, cryoglobulinemia.

Diagnosis:-
1. ANA (+) in 90% of cases, RF (+) in 75 % of patients with secondary disease.
2. Anti ribonucleoprotein antibodies (Anti SS-A (Ro) and Anti SS-B (La) antibodies) are positive.
3. Schirmer test to access tear production.
4. Rose Bengal stain shows damaged epithelium of cornea and conjunctiva.
5. Lip (minor salivary gland) biopsy shows lymphocytic infiltration.

Management:-
1. Pilocarpine or Cevimeline (enhance oral and ocular secretions via acetylcholine).
2. Artificial tears for dry eyes.
3. Good oral hygiene.
4. NSAIDs, Steroids, DMARDs for extra glandular manifestations.

Carcinoid syndrome

Vignette says a 55 year old woman presents to the clinic with chief complaints of intermittent facial flushing, diarrhea and wheezing over the past 6 months; She also reports of having occasional episodes of crampy abdominal pain along with nausea, vomiting and loose stools occurring 3-4 times a day; She also complains of unintentional weight loss of 8 kg, in past 6 months; Examination shows holosystolic murmur at the left sternal border on auscultation; Vital signs show blood pressure of 120/80 mm of Hg, pulse rate of 102 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 99.9 F; 24-hour urinary excretion of 5-HIAA is increased; MRI of abdomen and pelvis shows small bowel mass with multiple liver metastasis; Diagnosis?

Diagnosis is carcinoid syndrome.

Carcinoid syndrome occurs when a carcinoid tumor (i.e. neuroendocrine tumors) commonly located in the GI tract (e.g. small bowel) metastasizes to the liver as serotonin produced by the tumor cannot be metabolized by the liver and leads to the distinctive clinical features.

Presents with abdominal pain, bronchospasm, flushing and diarrhea. Carcinoid syndrome is associated with right sided valvular lesions (i.e. tricuspid regurgitation, pulmonic stenosis); Triggers include alcohol, stress and spicy food; Triad of dermatitis, dementia, and diarrhea due to niacin deficiency (as tryptophan is shunted towards production of serotonin).

Location of carcinoid tumors:- Bronchus> Ileum > Rectum > Appendix > Colon.

Diagnosis:-

1. 24-hour urinary excretion of 5-HIAA is increased.

2. CT/MRI of abdomen and pelvis to localize the primary or metastatic carcinoid tumors.

3. Octreotide scintigraphy to localize the primary or metastatic carcinoid tumors.

4. Neuroendocrine markers (i.e. chromogranin, synaptophysin) are elevated.

5. Echocardiography shows valvular heart disorders (i.e. tricuspid regurgitation, pulmonic stenosis).

Management:-

1. Avoid triggers, correct electrolytes abnormalities (due to chronic diarrhea), niacin supplementation, loperamide for diarrhea, beta agonists for bronchospasm and antihistamines for flushing. 

2. Somatostatin analogues (e.g. octreotide) for symptom control.

3. Surgical resection for localized tumors.

4. Liver directed therapies (e.g. hepatic artery embolization, radiofrequency ablation, targeted radiotherapy (i.e. smart bombs)) for liver metastases.

HY point:- Chromogranin A and synaptophysin are the most specific immunohistochemical markers for the neuroendocrine tumors (e.g. small cell carcinoma of lung, carcinoid tumor, pheochromocytoma and neuroblastoma).